Tri-aryl-substituted-ethane PDE4 inhibitors

ABSTRACT

Novel ethanes substituted with i) a phenyl, ii) a thiazole, and iii) a pyridyl moiety are PDE4 inhibitors.

This is a divisional of U.S. patent application Ser. No. 09/810,119,filed Mar. 16, 2001 now U.S. Pat. No. 6,399,636 which claims the benefitof U.S. Patent Application No. 60/191,668 filed Mar. 23, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that are tri-arylsubstituted ethanes. In particular, this invention is directed toethanes substituted with i) a phenyl, ii) a thiazole, and iii) a pyridylmoiety which are phosphodiesterase-4 inhibitors.

2. Related Background

Hormones are compounds that variously affect cellular activity. In manyrespects, hormones act as messengers to trigger specific cellularresponses and activities. Many effects produced by hormones, however,are not caused by the singular effect of just the hormone. Instead, thehormone first binds to a receptor, thereby triggering the release of asecond compound that goes on to affect the cellular activity. In thisscenario, the hormone is known as the first messenger while the secondcompound is called the second messenger. Cyclic adenosine monophosphate(adenosine 3′,5′-cyclic monophosphate, “cAMP” or “cyclic AMP”) is knownas a second messenger for hormones including epinephrine, glucagon,calcitonin, corticotrophin, lipotropin, luteinizing hormone,norepinephrine, parathyroid hormone, thyroid-stimulating hormone, andvasopressin. Thus, cAMP mediates cellular responses to hormones. CyclicAMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases (“PDE”) are a family of enzymes that metabolize 3′,5′cyclic nucleotides to 5′ nucleoside monophosphates, thereby terminatingcAMP second messenger activity. A particular phosphodiesterase,phosphodiesterase-4 (“PDE4”, also known as “PDE-IV”), which is a highaffinity, cAMP specific, type IV PDE, has generated interest aspotential targets for the development of novel anti-asthmatic andanti-inflammatory compounds. PDE4 is known to exist as at lease fourisoenzymes, each of which is encoded by a distinct gene. Each of thefour known PDE4 gene products is believed to play varying roles inallergic and/or inflammatory responses. Thus, it is believed thatinhibition of PDE4, particularly the specific PDE4 isoforms that producedetrimental responses, can beneficially affect allergy and inflammationsymptoms. It would be desirable to provide novel compounds andcompositions that inhibit PDE4 activity.

Inhibition of PDE4 activity is believed effective for the treatment ofosteoporosis by reducing bone loss. For example, Ken-ici Miyamoto etal., Biochem. Pharmacology, 54:613-617(1997) describes the effect of aPDE4 on bone loss. Therefore, it would be desirable to provide novelcompounds and compositions that inhibit PDE4 activity.

A major concern with the use of PDE4 inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in C. Burnouf et al., (“Burnouf”), Ann. Rep. In Med. Chem.,33:91-109(1998). B. Hughes et al., ×Br. J.Pharmacol.,118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys.,29:113-132(1998); S. B. Christensen et al., J.Med. Chem.,41:821-835(1998); and Burnouf describe the wide variation of theseverity of the undesirable side effects exhibited by various compounds.As described in M. D. Houslay et al., Adv. In Pharmacol.,44:225-342(1998) and D. Spina et al., Adv. In Pharmacol.,44:33-89(1998), there is great interest and research of therapeutic PDE4inhibitors.

U.S. Pat. Nos. 5,622,977, 5,710,160, 5,710,170, 5,798,373, 5,849,770,and International Patent Publication No. WO 99/50262 describetri-substituted aryl derivative PDE IV inhibitors, including tri-arylethane derivatives.

Compounds that include ringed systems are described by variousinvestigators as effective for a variety of therapies and utilities. Forexample, International Patent Publication No. WO 98/25883 describesketobenzamides as calpain inhibitors, European Patent Publication No. EP811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describesubstituted benzoylguanidine sodium channel blockers, U.S. Pat. No.5,736,297 describes ring systems useful as a photosensitive composition.International Patent Publication WO9422852 describes quinolines as PDE4inhibitors.

U.S. Pat. Nos. 5,491,147, 5,608,070, 5,739,144, 5,776,958, 5,780,477,5,786,354, 5,859,034, 5,866,593, 5,891,896, and International PatentPublication WO 95/35283 describe PDE4 inhibitors that aretri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No.5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S.Pat. No. 5,550,137 describes PDE4 inhibitors that arephenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478describes PDE4 inhibitors that are tetra-substituted phenyl derivatives.International Patent Publication WO 96/00215 describes substituted oximederivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describesPDE4 inhibitors that are cyclo(alkyl and alkenyl)phenylalkenyl (aryl andheteroaryl) compounds.

However, there remains a need for novel compounds and compositions thattherapeutically inhibit PDE4 with minimal side effects.

SUMMARY OF THE INVENTION

The present invention is directed to novel tri-aryl substituted ethanes.In particular, this invention is directed to ethanes substituted with i)a phenyl, ii) a thiazole, and iii) a pyridyl moiety which arephosphodiesterase-4 inhibitors. This invention also provides apharmaceutical composition which includes an effective amount of thenovel tri-aryl substituted ethanes and a pharmaceutically acceptablecarrier. This invention further provides a method of treatment inmammals of, for example, asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), eosinophilic granuloma, psoriasis and otherbenign or malignant proliferative skin diseases, endotoxic shock (andassociated conditions such as laminitis and colic in horses), septicshock, ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, infant respiratory distress syndrome, chronicobstructive pulmonary disease in animals, diabetes insipidus, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, arterialrestenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation,pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplantrejection and graft versus host disease, hypersecretion of gastric acid,bacterial, fungal or viral induced sepsis or septic shock, inflammationand cytokine-mediated chronic tissue degeneration, osteoarthritis,cancer, cachexia, muscle wasting, depression, memory impairment, tumourgrowth, cancerous invasion of normal tissues, osteoporosis, and boneloss by the administration of an effective amount of the novel ethanessubstituted with i) a phenyl, ii) a thiazole, and iii) a pyridyl moietywhich are phosphodiesterase-4 inhibitors

DETAILED DESCRIPTION OF THE INVENTION

A compound of this invention is represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with        1-4 independent halogen;    -   R² is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with        1-4 independent halogen;    -   R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of        which optionally substituted independently with 1-4 independent        halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen;    -   n is 0 or 1; and    -   when R³ and R⁴ are connected to each other through X, then R³        and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl.

According to one aspect, a compound of this invention is represented byformula (I) or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with        1-4 independent halogen;    -   R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of        which optionally substituted independently with 1-4 independent        halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen;    -   n is 0 or 1; and    -   when R³ and R⁴ are connected to each other through X, then R³        and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl.

According to one embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of        which optionally substituted independently with 1-4 independent        halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen;    -   n is 0 or 1; and    -   when R³ and R⁴ are connected to each other through X, then R³        and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl.

According to another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ is C₁₋₄alkyl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to yet another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ is C₃₋₆cycloalkyl, optionally substituted independently with        1-4 independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to an embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ is heteroaryl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to an embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ is phenyl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to still another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R³ and R⁴ are connected to each other through X;    -   R³ and R⁴ are each C₁alkyl;    -   X is C₀₋₄alkyl;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of        which optionally substituted independently with 1-4 independent        halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen;    -   n is 0 or 1; and    -   when R³ and R⁴ are connected to each other through X, then R³        and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl.

According to another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ is C₁₋₄alkyl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to yet another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ is C₃₋₆cycloalkyl, optionally substituted independently with        1-4 independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to an embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ is heteroaryl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to an embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ is phenyl, optionally substituted independently with 1-4        independent halogen or C₁₋₆alkyl;    -   R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4        independent halogen;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

According to still another embodiment of this aspect,

-   -   R¹ is C₁₋₆alkyl, optionally substituted with 1-4 independent        halogen;    -   R² is C₃₋₆cycloalkyl, optionally substituted with 1-4        independent halogen;    -   R³ and R⁴ are connected to each other through X;    -   R³ and R⁴ are each C₁alkyl;    -   X is C₀₋₄alkyl;    -   R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl        optionally substituted with 1-4 independent halogen; and    -   n is 0 or 1.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic substituent that is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and napthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁-C₂alkyl length to the oxyconnecting atom.

The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent.

The term “hetero” unless specifically stated otherwise includes one ormore N, O, or S atoms. Heterocycloalkyl and heteroaryl are ring systemsthat contain one or more O, S, or N atoms in the ring, includingmixtures of such atoms. The hetero atoms replace ring carbon atoms.Thus, for example, a heterocycloC₅alkyl is a five member ring containingfrom 5 to no carbon atoms. The term “heteroaryl” means an aryl groupthat has at least one heteroatom in the ring. The preferred heteroarylgroups are 5 and 6 member rings having 1-4 heteroatoms independentlyselected from N, O, or S.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

The term “halogen” includes fluorine, chlorine, bromine and iodineatoms.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula (I) is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula (I) and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula (I) (or pharmaceutically acceptablesalts thereof) as an active ingredient, a pharmaceutically acceptablecarrier and optionally other therapeutic ingredients or adjuvants. Suchadditional therapeutic ingredients include, for example, i) Leukotrienereceptor antagonists, ii) Leukotriene biosynthesis inhibitors, and iii)M2/M3 antagonists. The compositions include compositions suitable fororal, rectal, topical, and parenteral (including subcutaneous,intramuscular, and intravenous) administration, although the mostsuitable route in any given case will depend on the particular host, andnature and severity of the conditions for which the active ingredient isbeing administered. The pharmaceutical compositions may be convenientlypresented in unit dosage form and prepared by any of the methods wellknown in the art of pharmacy.

Creams, ointments, jellies, solutions, or suspensions containing thecompound of Formula I can be employed for topical use. Mouth washes andgargles are included within the scope of topical use for the purposes ofthis invention.

Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weightper day are useful in the treatment of conditions such as asthma,chronic bronchitis, chronic obstructive pulmonary disease (COPD),eosinophilic granuloma, psoriasis and other benign or malignantproliferative skin diseases, endotoxic shock (and associated conditionssuch as laminitis and colic in horses), septic shock, ulcerativecolitis, Crohn's disease, reperfusion injury of the myocardium andbrain, inflammatory arthritis, chronic glomerulonephritis, atopicdermatitis, urticaria, adult respiratory distress syndrome, infantrespiratory distress syndrome, chronic obstructive pulmonary disease inanimals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis,vernal conjunctivitis, arterial restenosis, ortherosclerosis,atherosclerosis, neurogenic inflammation, pain, cough, rheumatoidarthritis, ankylosing spondylitis, transplant rejection and graft versushost disease, hypersecretion of gastric acid, bacterial, fungal or viralinduced sepsis or septic shock, inflammation and cytokine-mediatedchronic tissue degeneration, osteoarthritis, cancer, cachexia, musclewasting, depression, memory impairment, tumour growth and cancerousinvasion of normal tissues which are responsive to PDF4 inhibition, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, inflammation may be effectively treated by the administrationof from about 0.01 mg to 50 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.5 mg to about 3.5 g per patientper day. Further, it is understood that the PDE4 inhibiting compounds ofthis invention can be administered at prophylactically effective dosagelevels to prevent the above-recited conditions.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

In practice, the compounds represented by Formula (I), orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula (I), or pharmaceutically acceptablesalts thereof, may also be administered by controlled release meansand/or delivery devices. The compositions may be prepared by any of themethods of pharmacy. In general, such methods include a step of bringinginto association the active ingredient with the carrier that constitutesone or more necessary ingredients. In general, the compositions areprepared by uniformly and intimately admixing the active ingredient withliquid carriers or finely divided solid carriers or both. The productcan then be conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula (I). The compounds of Formula (1), orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0. 1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula (I) of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula (I), or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and pharmaceutical compositions of this invention havebeen found to exhibit biological activity as PDE4 inhibitors.Accordingly, another aspect of the invention is the treatment in mammalsof, for example, asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), eosinophilic granuloma, psoriasis and otherbenign or malignant proliferative skin diseases, endotoxic shock (andassociated conditions such as laminitis and colic in horses), septicshock, ulcerative colitis, Crohn's disease, reperfusion injury of themyocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, adult respiratorydistress syndrome, chronic obstructive pulmonary disease in animals,diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernalconjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis,neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease,hypersecretion of gastric acid, bacterial, fungal or viral inducedsepsis or septic shock, inflammation and cytokine-mediated chronictissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting,depression, memory impairment, tumour growth and cancerous invasion ofnormal tissues—maladies that are amenable to amelioration throughinhibition of the PDE4 isoenzyme and the resulting elevated cCAMPlevels—by the administration of an effective amount of the compounds ofthis invention. The term “mammals” includes humans, as well as otheranimals such as, for example, dogs, cats, horses, pigs, and cattle.Accordingly, it is understood that the treatment of mammals other thanhumans is the treatment of clinical correlating afflictions to thoseabove recited examples that are human afflictions.

Further, as described above, the compound of this invention can beutilized in combination with other therapeutic compounds. In particular,the combinations of the PDE4 inhibiting compound of this invention canbe advantageously used in combination with i) Leukotriene receptorantagonists, ii) Leukotriene biosynthesis inhibitors, or iii) M2/M3antagonists.

Assays Demonstrating Biological Activity LPS and FMLP-Induced TNF-α andLTB₄ Assays in Human Whole Blood

Whole blood provides a protein and cell-rich milieu appropriate for thestudy of biochemical efficacy of anti-inflammatory compounds such asPDE4-selective inhibitors. Normal non-stimulated human blood does notcontain detectable levels of TNF-α and LTB₄. Upon stimulation with LPS,activated monocytes express and secrete TNF-α up to 8 hours and plasmalevels remain stable for 24 hours. Published studies have shown thatinhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibitionand/or enhanced adenylyl cyclase activity occurs at the transcriptionallevel. LTB₄ synthesis is also sensitive to levels of intracellular cAMPand can be completely inhibited by PDE4-selective inhibitors. As thereis little LTB₄ produced during a 24 hour LPS stimulation of whole blood,an additional LPS stimulation followed by fMLP challenge of human wholeblood is necessary for LTB₄ synthesis by activated neutrophils. Thus, byusing the same blood sample, it is possible to evaluate the potency of acompound on two surrogate markers of PDE4 activity in the whole blood bythe following procedure.

Fresh blood was collected in heparinized tubes by venipuncture fromhealthy human volunteers (male and female). These subjects had noapparent inflammatory conditions and had not taken any NSAIDs for atleast 4 days prior to blood collection. 500 μL aliquots of blood werepre-incubated with either 2 μL of vehicle (DMSO) or 2 μL of testcompound at varying concentrations for 15 minutes at 37° C. This wasfollowed by the addition of either 10 μL vehicle (PBS) as blanks or 10μL LPS (1 μg/mL final concentration, #L-2630 (Sigma Chemical Co., St.Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (inPBS)). After 24 hours of incubation at 37° C., another 10 μL of PBS(blank) or 10 μL of LPS (1 μg/mL final concentration) was added to bloodand incubated for 30 minutes at 37° C. The blood was then challengedwith either 10 μL of PBS (blank) or 10 μL of fMLP (1 μM finalconcentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15minutes at 37° C. The blood samples were centrifuged at 1500×g for 10minutes at 4° C. to obtain plasma. A 50 μL aliquot of plasma was mixedwith 200 μL methanol for protein precipitation and centrifuged as above.The supernatant was assayed for LTB₄ using an enzyme immunoassay kit(#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to themanufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS)using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) accordingto manufacturer's procedure. The IC₅₀ values of Examples 1-36 generallyranged from 0.01 μM to 20 μM.

Anti-Allergic Activity In Vivo

Compounds of the invention have been tested for effects on anIgE-mediated allergic pulmonary inflammation induced by inhalation ofantigen by sensitized guinea pigs. Guinea pigs were initially sensitizedto ovalbumin under mild cyclophosphamide-induced immunosuppression, byintraperitoneal injection of antigen in combinations with aluminumhydroxide and pertussis vaccine. Booster doses of antigen were given twoand four weeks later. At six weeks, animals were challenged withaerosolized ovalbumin while under cover of an intraperitoneallyadministered anti-histamine agent (mepyramine). After a further 48 h,bronchial alveolar lavages (BAL) were performed and the numbers ofeosinophils and other leukocytes in the BAL fluids were counted. Thelungs were also removed for histological examination for inflammatorydamage. Administration of compounds of the Examples (0.001-10 mg/kg i.p.or p.o.), up to three times during the 48 h following antigen challenge,lead to a significant reduction in the eosinophilia and the accumulationof other inflammatory leukocytes. There was also less inflammatorydamage in the lungs of animals treated with compounds of the Examples.

SPA Based PDE Activity Assay Protocol

Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IVcAMP-specific phosphodiesterases were screened in a 96-well plate formatas follows:

In a 96 well-plate at 30° C. was added the test compound (dissolved in 2μL DMSO), 188 mL of substrate buffer containing [2,8- ³H] adenosine3′,5′-cyclic phosphate (cAMP, 100 nM to 50 μM), 10 mM MgCl₂, 1 mM EDTA,50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 mLof human recombinant PDE4 (the amount was controlled so that 10% productwas formed in 10 min.). The reaction was stopped after 10 min. by theaddition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc.,Piscataway, N.J.). The product AMP generated was quantified on a WallacMicrobeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg, Md.).The signal in the absence of enzyme was defined as the background. 100%activity was defined as the signal detected in the presence of enzymeand DMSO with the background subtracted. Percentage of inhibition wascalculated accordingly. IC₅₀ value was approximated with a non-linearregression fit using the standard 4-parameter/multiple binding sitesequation from a ten point titration.

The IC₅₀ values of Examples 1-36 were determined with 100 nM cAMP usingthe purified GST fusion protein of the human recombinantphosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9expression system. The IC₅₀ values of Examples 1-36 generally rangedfrom 0.05 nm to 200 nm.

The examples that follow are intended as an illustration of certainpreferred embodiments of the invention and no limitation of theinvention is implied.

Unless specifically stated otherwise, the experimental procedures wereperformed under the following conditions. All operations were carriedout at room or ambient temperature—that is, at a temperature in therange of 18-25° C. Evaporation of solvent was carried out using a rotaryevaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) witha bath temperature of up to 60° C. The course of reactions was followedby thin layer chromatography (TLC) and reaction times are given forillustration only. Melting points are uncorrected and ‘d’ indicatesdecomposition. The melting points given are those obtained for thematerials prepared as described. Polymorphism may result in isolation ofmaterials with different melting points in some preparations. Thestructure and purity of all final products were assured by at least oneof the following techniques: TLC, mass spectrometry, nuclear magneticresonance (NMR) spectrometry or microanalytical data. Yields are givenfor illustration only. When given, NMR data is in the form of delta (δ)values for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as internal standard, determined at300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventionalabbreviations used for signal shape are: s. singlet; d. doublet; t.triplet; m. multiplet; br. broad; etc. In addition, “Ar” signifies anaromatic signal. Chemical symbols have their usual meanings; thefollowing abbreviations have also been used: v (volume), w (weight),b.p. (boiling point), m.p. (melting point), L (liter(s)), mL(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol(millimoles), eq (equivalent(s)).

Methods of Synthesis

The compounds of Formula (I) of the present invention can be preparedaccording to the synthetic routes outlined in Schemes 1 to 3 below andby following the methods described therein. It is obvious to one skilledin the art that resolution of compounds bearing stereogenic centers,such as VII, XIII to XVI for example, or compounds of Formula I and Ia,can be accomplished by one of several methods, including HPLC with achiral column, or formation and crystallization of a salt prepared byreaction of the compound with a chiral acid or base. The substituentsare the same as in Formula (I) except where defined otherwise. It isapparent that RP is readily incorporated into the compounds of thisinvention by starting with the appropriately substituted alkylpyridylacetate reactant.

Scheme 1

The thiazole tertiary alcohols of Formula I may be prepared in amulti-step sequence from the requisite dialkoxyaldehyde III and anappropriately substituted thiazole II as presented in Scheme 1 below.Addition of a metalated thiazole, prepared by regioselective metalationof thiazole II with a base such as n-butyllithium in a suitable solventsuch as ether or TBF, to III provides secondary alcohol IV. Conversionof IV into the corresponding secondary chloride or bromide V isaccomplished by reaction with an appropriate halogenating reagent, suchas thionyl chloride or thionyl bromide, and an organic base, such aspyridine, diisopropylethylamine or triethylamine, in an organic solventsuch as dichloromethane or toluene. Alkylation of the anion derived fromdeprotonation of an alkyl pyridylacetate with an appropriate base, suchas lithium, sodium or potassium bis(trimethylsilyl)amide, with thehalide V in an appropriate organic solvent such as TBF and/or HMPA(hexamethylphosphoramide), provides the ester VI. Ester VI isdecarboxylated by one of several methods to give the pyridine VII.

In one method, heating VI in the presence of aqueous hydroxide, such assodium hydroxide, in a mixture of protic and aprotic organic solvents,such as methanol or ethanol and THF, followed by acidification of theintermediate carboxylic acid with mineral acid, such a hydrochloricacid, provides VII. Alternatively, heating the carboxylic acid in anorganic solvent such as dimethylsulfoxide provides VII.

Removal of the alcohol protecting group, for example by treating with anorganic acid such as trifluoroacetic acid in an organic solvent such adichloromethane (if P=2-(trimethylsilyl)ethoxymethoxy), affords thepyridines of Formula Ia of the present invention. Reaction of Ia with anoxidizing agent, such as m-CPBA (meta-chloroperoxybenzoic acid) or MMPP(monoperoxyphthalic acid, magnesium salt) provides the N-oxides ofFormula I of the present invention. Alternatively, oxidation of VII asdescribed above for Ia, followed by deprotection affords the N-oxides ofFormula I of the present invention.

Scheme 2

Alternatively, compounds of Formula I can be prepared using the routedescribed in Scheme 2 below. Alkylation of the anion derived fromdeprotonation of an alkyl pyridylacetate N-oxide with an appropriatebase, such as lithium, sodium or potassium bis(trimethylsilyl)amide,with the secondary halide V in an appropriate organic solvent such asTHF and/or HMPA, provides the ester VIII. Decarboxylation anddeprotection as described in Scheme 1 provides the N-oxides of Formula Iof the present invention.

Scheme 3

The thiazole tertiary alcohols of Formula I may also be prepared in amulti-step sequence from the requisite dialkoxyaldehyde III and anappropriately substituted thiazole IX as presented in Scheme 3 below viathe intermediacy of the aldehyde XIV. Addition of a metalated thiazole,prepared by regioselective metalation of thiazole IX in a suitablesolvent such as ether or THF, to III provides secondary alcohol X.Conversion of X into the corresponding secondary chloride or bromide XIis accomplished by reaction with an appropriate halogenating reagent,such as thionyl chloride or thionyl bromide, and an organic base, suchas pyridine, diisopropylethylamine or triethylamine, in an organicsolvent such as dichloromethane or toluene. Alkylation of the anionderived from deprotonation of an alkyl pyridylacetate with anappropriate base, such as lithium, sodium or potassiumbis(trimethylsilyl)amide, with the halide XI in an appropriate organicsolvent such as THF and/or HMPA, provides the ester XII. Ester XII isdecarboxylated as described in Scheme 1 above to give XIII. Removal ofthe aldehyde protecting group by reaction of XIII with an acid, such ashydrochloric acid or p-toluenesulfonic acid, provides aldehyde XIV.Treatment of aldehyde XIV with a nucleophilic reagent, such as anorganolithium, organocerium or Grignard reagent, in an organic solvent,such as ether or THF, provides the secondary alcohol XV. Oxidation of XVwith an oxidizing agent, such as manganese dioxide or by Swem oxidation,affords ketone XVI. Further reaction of ketone XVI with a secondnucleophilic reagent, such as an organolithium, organocerium or Grignardreagent, in an organic solvent such as ether or THF, provides thepyridines of Formula Ia of the present invention. Reaction of Ia with anoxidizing agent, such as m-CPBA or MMPP provides the N-oxides of FormulaI of the present invention.

EXAMPLES 1-36

Examples 1-36 are summarized in the table below:

Example R1 R2 R3 R4 Pyridine n  1 CHF₂ CHF₂ CH₃ CH₃ 4-Pyr 1  2 CHF₂ CHF₂CH₃ CH₃ 4-Pyr 1  3 CHF₂ CHF₂ CF₃ H 4-Pyr 0  4 CHF₂ CHF₂ CF₃ H 4-Pyr 1  5CHF₂ CHF₂ CF₃ CF₃ 4-Pyr 0  6 CHF₂ CHF₂ CF₃ CF₃ 4-Pyr 1  7 CHF₂ CHF₂ CF₃CH₃ 4-Pyr 1  8 CHF₂ CHF₂ Ph H 4-Pyr 1  9 CHF₂ CHF₂ Ph CH₃ 4-Pyr 1 10CHF₂ CHF₂ Ph CF₃ 4-Pyr 1 11 CHF₂ CHF₂ Ph Et 4-Pyr 1 12 CHF₂ CHF₂ c-Hex H4-Pyr 0 13 CHF₂ CHF₂ c-Hex CF₃ 4-Pyr 1 14 CHF₂ CHF₂ 4-EtPh CH₃ 4-Pyr 115 CHF₂ CHF₂ 4-EtPh CF₃ 4-Pyr 1 16 CHF₂ CHF₂ 4-FPh CH₃ 4-Pyr 1 17 CHF₂CHF₂ 4-FPh CF₃ 4-Pyr 1 18 CHF₂ CHF₂ 2-(5-Br)Pyr CF₃ 4-Pyr 1 19 CHF₂ CHF₂3-(6-Br)Pyr CF₃ 4-Pyr 1 20 CHF₂ CHF₂ —(CH₂)₃— 4-Pyr 1 21 CHF₂ CHF₂—(CH₂)₅— 4-Pyr 1 22 CHF₂ c-but CH₃ CH₃ 4-Pyr 1 23 CHF₂ c-but CH₃ CH₃4-Pyr 1 24 CHF₂ c-but CF₃ CF₃ 4-Pyr 0 25 CHF₂ c-but CF₃ CF₃ 4-Pyr 1 26CHF₂ c-but CH₃ CH₃ 3-Pyr 0 27 CHF₂ c-but CH₃ CH₃ 3-Pyr 0 28 CHF₂ c-butCH₃ CH₃ 3-Pyr 1 29 CHF₂ c-but CH₃ CH₃ 3-Pyr 1 30 CHF₂ c-but CF₃ CF₃3-Pyr 1 31 CHF₂ c-but CF₃ CF₃ 3-Pyr 1 32 CHF₂ c-but CF₃ CF₃ 2-Pyr 1 33CHF₂ c-pr CH₃ CH₃ 4-Pyr 1 34 CHF₂ c-pr CF₃ CF₃ 3-Pyr 1 35 CHF₂ c-pr CF₃CF₃ 3-Pyr 1 36 CHF₂ c-pr CF₃ CF₃ 3-Pyr 1

In the table above, “c-but” represents cyclobutyl, “c-pr” representscyclopropyl, “c-pent” represents cyclopentyl, “c-Hex” representscyclohexyl, “4-EtPh” represents 4-ethylphenyl, “4-FPh” represents4-fluorophenyl, “Ph” represents phenyl, “Pyr” represents pyridyl,“2-(5-Br)Pyr” represents 2-(5-bromo)pyridyl, and “3-(6-Br)Pyr”represents 3-(6-bromo)pyridyl.

Examples

All examples are mixtures of stereoisomers, either racemic mixtures(indicated as (±)) or racemic mixtures of diastereomers (indicated as(±/±)) unless stated otherwise. In those cases in which thestereoisomers have been separated, they are so indicated by Enantiomer1, 2 etc. or Diastereomer 1, 2 etc.

Preparation of Intermediates Intermediate 1(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-formyl)thiazolyl]ethyl}pyridine

Step 1: 2-(1,3-Dioxan-2-yl)thiazole

A solution of 2-formylthiazole (10 g, 88 mmol), 1,3-propanediol (8 mL)and p-TsOH (100 mg) in benzene (110 mL) was heated at reflux temperaturefor 15 h with removal of water using a Dean-Stark apparatus. The mixturewas cooled to room temperature and washed twice with sat. aq. NaHCO₃,twice with water and concentrated. The resulting solid was crystallizedfrom hexane to provide 2-(1,3-Dioxan-2-yl)thiazole as a tan solid (10.4g).

Step 2:(±)-3,4-Bis(difluoromethoxy)phenyl-5-[2-(1,3-dioxan-2-yl)]thiazolylcarbinol

To a solution of n-BuLi (37.2 mL of a 2.5M solution in hexane, 93 mmol)at −65° C. was added a solution of 2-(1,3-dioxan-2-yl)thiazole from Step1 (17.6 g, 93 mmol) in anhydrous ether (200 mL) over 30 min, maintainingthe internal temperature at −65 to −70° C. After a further 20 min,3,4-bis(difluoromethoxy)benzaldehyde (22.1 g, 93 mmol) in anhydrousether (150 mL) was added over 30 min. The mixture was stirred at −70° C.for 1 h and then sat. aq. NH₄Cl (200 mL) was added. The mixture wasallowed to warm to room temperature and then partitioned with ether andwater. The organic layer was dried (MgSO₄) and concentrated. Flashchromatography of the residue (silica gel; ethyl acetate/hexane 2:1)provided(±)-3,4-Bis(difluoromethoxy)phenyl-5-[2-(1,3-dioxan-2-yl)]thiazolylcarbinolas a yellow syrup (18.4 g).

Step 3:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1,3-dioxan-2-yl))thiazolyl]ethyl}pyridine

To a solution of pyridine (10.7 mL, 132 mmol) in toluene (125 mL) at 0°C. was slowly added thionyl bromide (5.12 mL, 66 mmol) and the resultingmixture was stirred at this temperature for 10 min. To this mixture wasslowly added, over 10 min, a solution of(±)-3,4-bis(difluoromethoxy)phenyl-5-[2-(1,3-dioxan-2-yl)]thiazolylcarbinolfrom Step 2 (18 g, 44 mmol) in toluene (75 mL). The mixture was stirredat 0° C. for 45 min and then the solids that were formed were allowed tosettle. The supernatant was filtered through a pad of silica gelpre-wetted with ethyl acetate. The solids were washed with ethyl acetateand filtered as well. The combined filtrates were concentrated at a bathtemperature <40° C. to provide the crude bromide that was usedimmediately.

To a solution of ethyl 4-pyridylacetate (26.9 mL, 176 mmol) in THF (250mL) and HMPA (30.6 mL, 176 mmol) at 0° C. was added sodiumbis(trimethylsilyl)amide (176 mL of a 1M solution in THF, 176 mmol). Theresulting mixture was stirred for 45 min and then a THF (140 mL)solution of the bromide prepared above was added over 20 min and thenstirred for 15 h at 25° C. The stirred mixture was poured into sat.NH₄Cl (500 mL) and extracted twice with ethyl acetate. The combinedorganics were washed successively with water (3×), brine, dried (MgSO₄)and concentrated to give a thick oil. This material was dissolved in amixture of THF/MeOH/1N NaOH (2:1:1, 1 L) and the mixture was heated atreflux for 1 h. The volatiles were removed on the rotovap, water (250mL) was added, and then 1N HCl was slowly added, bringing the pH toapproximately 5. The mixture was extracted three times with ethylacetate and the combined organics were washed with water (3×), dried(MgSO₄) and concentrated. Flash chromatography of the residue (silicagel; ethyl acetate/ethanol 95:5) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1,3-dioxan-2-yl))thiazolyl]ethyl}pyridineas a yellow syrup (15.2 g).

Step 4:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-formyl)thiazolyl]ethyl}pyridine

A mixture of(±)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-(1,3-dioxan-2-yl))thiazolyl]ethyl}pyridinefrom Step 3 (15 g, 31 mmol) and 2N HCl (150 mL) in THF (200 mL) washeated at reflux for 20 h. The mixture was cooled to room temperature,diluted with water (500 mL) and then the pH was adjusted to ˜8 by theaddition of 2.5N NaOH. The mixture was extracted with ether (3×) and thecombined organics were washed with water (2×), brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel; ethylacetate) provided the(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-formyl)thiazolyl]ethyl}pyridineas an amber syrup (10.1 g).

Thiazole 1 2-{1-Methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazole

Step 1: 2-[(1-Hydroxy-1-methyl)ethyl]thiazole

To a solution of thiazole (5 g, 58.8 mmol) in anhydrous ether at −78° C.was slowly added over 5 min n-BuLi (40.4 mL of a 1.65M solution inhexane, 64.2 mmol). The resulting mixture was stirred for 20 min andthen acetone (5.6 mL, 76.4 mmol) was slowly added. After 25 min, themixture was poured into 25% aq. NH₄OAc and the resulting mixture wasextracted with ethyl acetate (5×). The combined organics were washedwith brine, dried (MgSO₄) and concentrated. The residual oil (8.9 g) wasused as such in the next reaction.

Step 2: 2-{1-Methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazole

To a solution of the alcohol 2-[(1-Hydroxy-1-methyl)ethyl]thiazole fromStep 1 (8.9 g, 59 mmol) and Hunig's base (26 mL, 148 mmol) indichloromethane (75 mL) at room temperature was added2-(trimethylsilyl)ethoxymethyl chloride (12.5 mL, 70.8 mmol). Theresulting solution was stirred at room temperature for 1 h, at 50° C.for 3.5 h and finally at room temperature for 15 h. The mixture waspoured into 25% aq. NH₄OAc (200 mL) and the resulting mixture wasextracted with ethyl acetate (3×). The combined organics were washedwith brine, dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel; hexane/ethyl acetate 9:1) provided the2-{1-Methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazole product asa yellow liquid (9.6 g).

Thiazole 22-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazole

Step 1: 2-[(1-Hydroxy-1-trifluoromethyl)-2,2,2-trifluoroethyl]thiazole

To a solution of n-BuLi (425 μL of a 1.3M solution in hexane, 552 mmol)in anhydrous ether (400 mL) at −78° C. was slowly added over 45 min asolution of thiazole (42.7 g, 502 mmol) in anhydrous ether (400 mL). Theresulting mixture was stirred for 15 min and then hexafluoroacetone wasbubbled into the mixture for 30 min with the bath temperature maintainedbetween −60 to −70° C. The mixture was allowed to warm to roomtemperature and then poured into 25% aq. NH₄OAc. The resulting mixturewas extracted with ether and then the aqueous phase was acidified to ˜pH4 with conc. HCl. The aqueous phase was extracted with ether (2×). Thecombined organics were washed with brine, dried (Na₂SO₄) andconcentrated at <40° C. The residual liquid was distilled at ˜10 mm/Hgand the fractions distilling from 50 to 100° C. was collected. The2-[(1-Hydroxy-1-trifluoromethyl)-2,2,2-trifluoroethyl]thiazole compound(93 g) was obtained as a liquid and used as such in the next reaction.

Step 2:2-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazole

To a solution of the alcohol from Step 1 (93 g, 382 mmol) and Hunig'sbase (133 mL, 764 mmol) in dichloromethane (1.2 L) at 0° C. was added2-(trimethylsilyl)ethoxymethyl chloride (88 mL, 497 mmol) over 15 min.The resulting solution was stirred at room temperature for 15 h. Themixture diluted with ether (1 L) and then was poured into 25% aq. NH₄OAc(500 mL). The phases were separated and the aqueous phase was extractedwith ether. The combined organics were washed with brine, dried (Na₂SO₄)and concentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 95:5 to 9:1) provided2-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazoleas a yellow liquid (99 g).

Thiazole 32-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazole

Step 1: 2-[(1-Hydroxy-1-trifluoromethyl)ethyl]thiazole

To a solution of n-BuLi (107 mL of a 1.2 M solution in hexane, 129 mmol)in anhydrous ether (100 mL) at −78° C. was slowly added a solution ofthiazole (10 g, 117 mmol) in anhydrous ether (100 mL). The resultingmixture was stirred for 20 min and then 1,1,1-trifluoroacetone (12.5 mL,140 mmol) was added over 5 min. The mixture was stirred for 1 h at −78°C. and then allowed to warm for 15 min. Sat. aq. NH₄Cl was added and thephases were separated. The aqueous phase was acidified to pH 1 with 6NHCl and was extracted with ether. The combined organics were washed withbrine, dried (Na₂SO₄) and concentrated. The residual liquid (12 g) wasused as such in the next reaction.

Step 2:2-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazole

To a solution of the alcohol2-[(1-Hydroxy-1-trifluoromethyl)ethyl]thiazole from Step 1 (3 g, 15.2mmol) in DMF (75 mL) at 0° C. was added sodium hydride (170 mg, 16.7mmol) in two portions. The mixture was stirred at 0° C. for 15 min, atroom temperature for 15 min and then 2-(trimethylsilyl)ethoxymethylchloride (2.7 mL, 15.2 mmol) was added over 5 min. The resultingsolution was stirred at room temperature for 1 h and then cooled to 0°C. 25% aq. NH₄OAc was added and the mixture was diluted with ether (300mL). The phases were separated and the organic phase was washed withwater (4×). The combined aqueous were re-extracted with ether. Thecombined organics were washed with brine, dried (Na₂SO₄) andconcentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 85:15 to 4:1) provided2-{1-Trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazoleas a yellow liquid (3.4 g).

Thiazole 4 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole

Step 1: 2-[(1-Hydroxy)cyclobutyl]thiazole

To a solution of n-BuLi (36 mL of a 2.5M solution in hexane, 90 mmol) inanhydrous ether (100 mL) at −78° C. was slowly added a solution ofthiazole (6.35 g, 74.6 mmol) in anhydrous ether (60 mL). The resultingmixture was stirred for 1 h and then cyclobutanone (10.4 g, 148 mmol) inether (20 mL) was added over 5 min. The mixture was stirred for 2 h at−78° C. and then sat. aq. NH₄Cl was added and the phases were separated.The aqueous phase was extracted with ethyl acetate (3×) and the combinedorganics were washed with water, brine, dried (MgSO₄) and concentrated.Flash chromatography of the residue (silica gel; hexane/ethyl acetate4:1 to 7:3) provided 2-[(1-Hydroxy)cyclobutyl]thiazole (5 g).

Step 2: 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole

To a solution of the alcohol 2-[(1-Hydroxy)cyclobutyl]thiazole from Step1 (5 g, 32 mmol) and Hunig's base (10.4 mL, 60 mmol) in dichloromethane(100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 1 h, washeated at reflux temperature for 3.5 h and finally was stirred at roomtemperature for 15 h. Sat. aq. NH₄Cl was added and the resulting mixturewas extracted with dichloromethane (3×). The combined organics werewashed with water, brine, dried (MgSO₄) and concentrated. Flashchromatography of-the residue (silica gel; dichloromethane todichloromethane/ethyl acetate 95:5) provided2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole (2 g).

Thiazole 5 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclohexyl}thiazole

Step 1: 2-[(1-Hydroxy)cyclohexyl]thiazole

To a solution of n-BuLi (22 mL of a 2.5M solution in hexane, 55 mmol) inanhydrous ether (60 mL) at −78° C. was slowly added a solution ofthiazole (3.94 g, 46 mmol) in anhydrous ether (30 mL). The resultingmixture was stirred for 1 h and then cyclohexanone (9.6 mL, 93 mmol) inether (25 mL) was added over 5 min. The mixture was stirred for 2.5 h at−78° C. and then sat. aq. NH₄Cl was added and the phases were separated.The aqueous phase was extracted with ethyl acetate (3×) and the combinedorganics were washed with water, brine, dried (MgSO₄) and concentrated.Flash chromatography of the residue (silica gel; hexane/ethyl acetate4:1 to 7:3) provided the 2-[(1-Hydroxy)cyclohexyl]thiazole compound (5.8g).

Step 2: 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclohexyl}thiazole

To a solution of the alcohol 2-[(1-Hydroxy)cyclohexyl]thiazole from Step1 (5.8 g, 32 mmol) and Hunig's base (14 mL, 67 mmol) in dichloromethane(100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 15 min,was heated at reflux temperature for 15 h and then cooled to roomtemperature. Sat. aq. NH₄Cl was added and the resulting mixture wasextracted with dichloromethane (3×). The combined organics were washedwith water, brine, dried (MgSO₄) and concentrated. Flash chromatographyof the residue (silica gel; hexane/ethyl acetate 7:3) provided2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclohexyl}thiazole (8 g).

Aldehyde 1 3-Cyclopropyloxy-4-difluoromethoxybenzaldehyde

Step 1: 3-(2-Chloro)ethoxy-4-difluoromethoxybenzaldehyde

A mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (77 g, 409 mmol),1-bromo-2-chloroethane (176 g, 1.23 mol) and Cs₂CO₃ (146 g, 449 mmol) inDMF (2 L) was stirred at 70° C. for 3 h and at 55° C. for 15 h. Themixture was cooled to room temperature and partitioned between ethylacetate (1 L) and water (2 L). The aqueous layer was extracted withethyl acetate (2×) and the combined organics were washed with water,dried (Na₂SO₄) and concentrated. Flash chromatography of the residue(silica gel; hexane/ethyl acetate 4:1 to 7:3) provided the3-(2-Chloro)ethoxy-4-difluoromethoxybenzaldehyde compound (87 g).

Step 2:3-(2-Chloro)ethoxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene

To a solution of the aldehyde3-(2-Chloro)ethoxy-4-difluoromethoxybenzaldehyde from Step 1 (87 g, 347mmol) in THF (1 L) and MeOH (200 mL) at 0° C. was added NaBH₄ (15.7 g,416 mmol) in 4 portions over 20 min. The resulting mixture was stirredat room temperature for 3 h, re-cooled to 0° C., and then sat. aq. NH₄Cl(50 mL) was carefully added over 10 min. The mixture was diluted withethyl acetate (500 mL). The mixture was partioned between 25% aq. NH₄OAc(1 L) and ethyl acetate (1 L) and the aqueous layer was extracted withethyl acetate (2×). The combined organics were washed with brine, dried(Na₂SO₄) and concentrated.

The residue was dissolved in dichloromethane (1 L) and 2,6-lutidine (60mL, 520 mmol) and cooled in an ice bath. Triisopropylsilyl triflate (102mL, 381 mmol) was slowly added and after addition was complete, themixture was stirred at room temperature for 2 h. A second aliquot oftriisopropylsilyl triflate (16 mL) was added and the mixture was stirredfor 15 h. The mixture was cooled to 0° C. and sat. aq. NaHCO₃ (50 mL)was added. Ether (1.5L) and 25% aq. NH₄OAc (1 L) were added and theaqueous layer was extracted with ether (2×). The combined organics werewashed with brine, dried (Na₂SO₄) and concentrated. Flash chromatographyof the residue (silica gel; hexane/ethyl acetate 98:2 to 95:5) providedthe3-(2-Chloro)ethoxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzenecompound (124 g).

Step 3:3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene

A mixture of the chloride,3-(2-Chloro)ethoxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene,from Step 2 (124 g, 303 mmol), 10N NaOH (300 mL, 3.03 mol) and Bu₄NHSO₄(102 g, 303 mmol) in benzene (1.3L) was heated at 65° C. for 4.5 h. Themixture was cooled to room temperature and was partitioned with 25% aq.NH₄OAc (500 mL). The aqueous phase was extracted with ether (2×) and thecombined organics were washed with brine, dried (Na₂SO₄) andconcentrated. The residual oil was dissolved in dichloromethane (1 L)and 2,6-lutidine (53 mL, 454 mmol) and cooled in an ice bath.Triisopropylsilyl triflate (98 mL, 363 mmol) was slowly added and afteraddition was complete, the mixture was stirred at room temperature for 3h. The mixture was cooled to 0° C. and sat. aq. NaHCO₃ (50 mL) wasadded. Ether (1.5 L) and 25% aq. NH₄OAc (500 mL) were added and theaqueous layer was extracted with ether (2×). The combined organics werewashed with brine, dried (Na₂SO₄) and concentrated. Flash chromatographyof the residue (silica gel; hexane/ethyl acetate 98:2 to 95:5) provided3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene (67g).

Step 4:3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene

To a solution of the alkene,3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene,from Step 3 (67 g, 179 mmol) and chloroiodomethane (78 mL, 1.07 mol) indichloromethane (1.5 L) at 5° C. (ice bath) was added diethyl zinc (55mL, 537 mmol) in 5 mL portions over 1.2 h. During the addition, theinternal temperature was maintained at <20° C. After the addition wascomplete, the mixture was stirred for 15 min and then the cooling bathwas removed and stirring was continued for a further 2.5 h. The mixturewas re-cooled to 5° C. (ice bath) and MeOH (2 mL) was added over 15 min,followed by the addition of water (30 mL) over 15 min and finally, theaddition of 6N HCl (5 mL). The mixture was partitioned between ether(IL) and water (500 mL). The aqueous layer was extracted with ether (500mL) and the combined organics were washed with brine, dried (Na₂SO₄) andconcentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 98:2 to 95:5) provided3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene(71 g).

Step 5: 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol

To a solution of the silyl ether,3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene,from Step 4 (70 g, 179 mmol) in TBF (700 mL) at room temperature wasadded TBAF (215 mL of a 1M solution in THF, 215 mmol) and the resultingmixture was stirred for 17 h. The mixture was partitioned between 25%aq. NH₄OAc (500 mL) and ethyl acetate (1 L) and the aqueous layer wasextracted with ethyl acetate (2×). The combined organics were washedwith brine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; hexane/ethyl acetate 3:2 to 1:1) provided the3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol compound (41 g).

Step 6: 3-Cyclopropyloxy-4-difluoromethoxybenzaldehyde

To a solution of the 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcoholfrom Step 5 (41 g, 179 mmol) in dichloromethane (1.2 L) was added MnO₂(220 g, 2.15 mol) in four portions over 2 days. When TLC indicated thereaction was complete, the mixture was diluted with ethyl acetate andfiltered through Celite® (available from Aldrich Chemical Company, Inc.,Milwaukee, Wis.), washing extensively with a succession of ethylacetate, dichloromethane, EtOH and toluene. The combined filtrates wereconcentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 3:1 to 7:3) provided the3-Cyclopropyloxy-4-difluoromethoxybenzaldehyde compound (3 1 g).

Example 1

(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 1 was prepared by the following procedure:

Step 1:(±)-3,4-Bis(difluoromethoxy)phenyl-5-{2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinol

To a solution of n-BuLi (5.6 mL of a 2.5M solution in hexane, 14 mmol)in anhydrous ether (50 mL) at −78° C. was added a solution of Thiazole 1(3.8 g, 14 mmol) in anhydrous ether (30 mL). After 70 min, a solution of3,4-bis(difluoromethoxy)benzaldehyde (2.8 g, 11.7 mmol) in anhydrousether (20 mL) was added. The resulting mixture was stirred at −78° C.for 2.5 h and then sat. aq. NH₄Cl was added. The mixture was allowed towarm to room temperature and then partitioned with ethyl acetate andwater. The aqueous phase was extracted with ethyl acetate (3×) and thecombined organics were washed with water, brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 4:1 to 7:3) provided the(±)-3,4-Bis(difluoromethoxy)phenyl-5-{2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinolproduct (3.85 g).

Step 2:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridine

To a solution of Hunig's base (1.7 mL, 9.8 mmol) in toluene (8 mL) at 0°C. was slowly added thionyl chloride (0.35 mL, 4.8 mmol) and theresulting mixture was stirred at this temperature for 5 min. To thismixture was slowly added a solution of(±)-3,4-bis(difluoromethoxy)phenyl-5-{2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinolfrom Step 1 (1.6 g, 3.2 mmol) in toluene (10 mL). The mixture wasstirred at 0° C. for 45 min and then mixture was filtered through a padof silica gel pre-wetted with ether, eluting with ether/hexane (4:1).The filtrate was concentrated to provide the crude chloride that wasused immediately.

To a solution of ethyl 4-pyridylacetate (2.12 g, 12.8 mmol) in THF (20mL) and HMPA (2.2 mL, 12.6 mmol) at room temperature was added sodiumbis(trimethylsilyl)amide (12.7 mL of a 1M solution in THF, 12.7 mmol).The resulting mixture was stirred for 30 min and then a THF (10 mL)solution of the crude chloride prepared above was added and then stirredfor 15 h at 25° C. Sat. aq. NH₄Cl was added, the layers were separatedand the aqueous phase was extracted with ethyl acetate (3×). Thecombined organics were washed successively with water (3×), brine, dried(MgSO₄) and concentrated to give a thick oil.

This material was dissolved in a mixture of THF/MeOH/water (2:2:1, 20mL), LiOH (1.5 g) was added and the mixture was heated at reflux for 1.5h. 1N HCl was slowly added, bringing the pH to approximately 6. Themixture was extracted three times with ethyl acetate and the combinedorganics were washed with water, brine, dried (MgSO₄) and concentrated.Flash chromatography of the residue (silica gel; ethyl acetate/hexane4:1) provided the(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineproduct as an oil (745 mg).

Step 3:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridine

To a solution of the protected alcohol from Step 2 (722 mg, 1.23 mmol)in dichloromethane (20 mL) was added TFA (3.8 mL, 49.3 mmol) and themixture was stirred at 0° C. for 2.5 h. Sat. aq. NH₄OAc was added andthe mixture was extracted with ethyl acetate (3×). The combined organicswere washed with water, brine, dried (MgSO₄) and concentrated. Flashchromatography of the residue (silica gel; ethyl acetate) provided the(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridineas an oil (394 mg).

Step 4:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

A mixture of the pyridine from Step 3 (192 mg, 0.42 mmol) and MMPP (209mg, 0.42 mmol) in dichloromethane (12 mL) and MeOH (1 mL) was stirred atroom temperature for 22 h. The mixture was filtered through Celite® andthe filtrate was concentrated. Chromatography of the residue (silicagel; dichloromethane/EtOH 4:1) provided the title(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridineN-oxide compound as a colorless foam (112 mg).

¹HNMR (400MHz, acetone-d₆): δ 1.51 (s, 6H), 3.45 (m, 2H), 4.75 (t, 1H),4.95 (br s, 1H), 6.95 (t, 1H), 6.96 (t, 1H), 7.19 (d, 2H), 7.30 (dd,2H), 7.38 (s, 1H), 7.94 (d, 2H).

Example 2

Chiral4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-Methyl)ethyl]thiazolyl}ethyl)pyridineN-oxide

Example 2 was prepared by the following procedure:

Step 1:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy)ethyl)thiazolyl]ethyl}pyridine

To a solution of Intermediate 1 (5.87 g, 13.8 mmol) in dichloromethane(170 mL) at 0° C. was added MeMgCl (20 mL of a 3M solution in THF, 60mmol) in three portions over 1 h. After a further 20 min, sat. aq. NH₄Clwas added and the mixture was extracted with ethyl acetate (3×). Thecombined organics were washed with water, brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel;acetone/dichloromethane 3:2) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy)ethyl)thiazolyl]ethyl}pyridineas an oil (5.1 1 g).

Step 2:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-acetyl)thiazolyl]ethyl}pyridine

A mixture of the alcohol,(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy)ethyl)thiazolyl]ethyl}pyridine,from Step 1 (5.07 g, 11.5 mmol) and MnO₂ (11 g, 126.5 mmol) indichloromethane (100 mL) was stirred at room temperature for 48 h. Themixture was filtered through Celite®, washing with dichloromethane, andthe filtrate was concentrated. Flash chromatography of the residue(silica gel; acetone/dichloromethane 1:3) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-acetyl)thiazolyl]ethyl}pyridineas an oil (4.87 g).

Step 3: Resolution of(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-acetyl)thiazolyl]ethyl}pyridine

A solution of(±)-4-{2-[3,4-bis(difluoromethoxy)phenyl]-2-[5-(2-acetyl)thiazolyl]ethyl}pyridine(Step 2; 4.87 g) in EtOH/hexane (21 mL, 2:3) was injected (3×7 mL) ontoa Chiralpak® AD (available from Chiral Technologies, Inc., Exton, Pa.)preparative (5 cm×50 cm) HPLC column (eluting with hexane/ethanol 3:1 at55 mL/min with UV detection at 270 nm). The enantiomers were separatedwith the faster eluting enantiomer having a retention time of 38 min(Enantiomer 1) and the slower eluting enantiomer (Enantiomer 2) having aretention time of 66 min. The eluants were concentrated to provide theenantiomers as brown gums: Enantiomer 1 (2.2 g) and Enantiomer 2 (2.3g).

Step 4: Chiral4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridine

A mixture of CeCl₃ (288 mg, 1.17 mmol; dried at 140° C. for 15 h) in TBF(12 mL) was heated at reflux for 3 h and then cooled to 0° C. MeMgCl(1.7 mL of a 3M solution in THF, 5.1 mmol) was added and the mixture wasstirred for 2 h. A solution of Enantiomer 2 (Step 3, 400 mg, 0.91 mmol)in toluene (4 mL) was added dropwise and the mixture was stirred for 1h. Sat. aq. NH₄Cl was added and the mixture was extracted with ethylacetate (3×). The combined organics were washed with water, brine, dried(MgSO₄) and concentrated. Flash chromatography of the residue (silicagel; acetone/dichloromethane 1:1) provided the Chiral4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridineproduct as an oil (383 mg).

Step 5: Chiral4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

A mixture of the pyridine from Step 4 (383 mg, 0.84 mmol) and MMPP (415mg, 0.89 mmol) in dichloromethane (25 mL) and MeOH (25 mL) was stirredat room temperature for 48 h. The mixture was filtered through Celite®and the filtrate was washed with sat. aq. NaHCO₃, water, brine, dried(MgSO₄) and concentrated. Chromatography of the residue (silica gel;ethyl acetate/EtOH 65:35) provided the title Chiral4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-methyl)ethyl)thiazolyl]ethyl}pyridinecompound as a colorless foam (306 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.51 (s, 6H), 3.45 (m, 2H), 4.75 (t, 1H),4.95 (br s, 1H), 6.95 (t, 1H), 6.96 (t, 1H), 7.19 (d, 2H), 7.30 (dd,2H), 7.38 (s, 1H), 7.94 (d, 2H).

Example 3

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridine

Example 3 was prepared by the following procedure. To a mixture ofIntermediate 1 (1.24 g, 2.9 mmol) and trimethyl(trifluoromethyl)silane(0.9 mL, 6.5 mmol) in THF (15 mL) at 0° C. was added TBAF (0.13 mL of a1M solution in THF, 0.13 mmol). After 1 h, 1 M HCl (10 mL) was added andthe mixture was stirred for 1.5 h at room temperature. The mixture wasbasified with sat. aq. Na₂CO₃ and then extracted with ethyl acetate(3×). The combined organics were dried (MgSO₄) and concentrated.Chromatography of the residue (silica gel; acetone/toluene 3:7 to 1:1)provided the title compound as a colorless foam (892 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.51 (m, 2H), 4.90 (t, 1H), 5.43 (m, 1H),6.64 (br s, 1H), 6.94 (t, 1H), 6.95 (t, 1H), 7.12-7.41 (m, 5H), 7.66 (d,1H), 8.38 (m, 2H).

Example 4

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 4 was prepared by the following procedure. A mixture of thepyridine from Example 3 (166 mg, 0.34 mmol) and MMPP (99 mg, 0.35 mmol)in dichloromethane (12 mL) and MeOH (3 mL) was stirred at roomtemperature for 48 h. An additional 25 mg of MMPP was added and themixture was heated at reflux temperature for 5 h. The mixture wasfiltered through Celite®, 1N NaOH was added and the mixture wasextracted with ethyl acetate (3×). The combined organics were dried(MgSO₄) and concentrated. Chromatography of the residue (silica gel;dichloromethane/MeOH 9:1) provided the title compound as a colorlessfoam (106 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.51 (m, 2H), 4.87 (t, 1H), 5.43 (m, 1H),6.89 (br s, 1H), 6.96 (t, 2H), 7.22 (d, 2H), 7.33 (m, 2H), 7.41 (d, 1H),7.68 (m, 1H), 7.96 (d, 2H).

Example 5

(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridine

Example 5 was prepared by following the procedures described in Example1, Steps 1 to 3, but substituting Thiazole 2 for Thiazole 1. Flashchromatography silica gel; toluene/acetone 7:3 to 3:2 provided the titleproduct as a foam (208 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.55 (m, 2H), 4.96 (t, 1H), 6.94 (t, 1H),6.96 (t, 1H), 7.20 (d, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.42 (s, 1H),7.81 (s, 1H), 8.20 (br s, 1H), 8.38 (d, 2H).

Example 6

(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 6 was prepared by following the procedures described in Example1, Step 4, but substituting Example 5 for the pyridine from Example 1,Step 3. The title compound (flash chromatography silica gel;dichloromethane/MeOH 9:1) was obtained as a foam (100 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.55 (m, 2H), 4.91 (t, 1H), 6.95 (t, 2H),7.22 (d, 2H), 7.32 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.80 (s, 1H),7.96 (d, 2H), 8.50 (br s, 1H).

Example 7

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 7 was prepared by the following procedure:

Step 1:(±/±)-3,4-Bis(difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinol

To a solution of Thiazole 3 (3.4 g, 10.4 mmol) in anhydrous THF (30 mL)at −78° C. was added n-BuLi (8.7 mL of a 1.2M solution in hexane, 10.4mmol) over 10 min. After 30 min, a solution of3,4-bis(difluoromethoxy)benzaldehyde (2.7 g, 10.4 mmol) in anhydrous THF(30 mL) was added via cannula. The mixture was stirred at −78° C. for 1h, the cooling bath was removed and then, after 15 min, sat. aq. NH₄Clwas added. The mixture was partitioned with ethyl acetate and water. Theaqueous phase was extracted with ethyl acetate (3×) and the combinedorganics were washed with brine, dried (Na₂SO₄) and concentrated. Flashchromatography of the residue (silica gel; hexane/ethyl acetate 7:3 to3:2) provided(±/±)-3,4-Bis(difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinol(5.66 g).

Step 2:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridine

To a solution of pyridine (1.6 mL, 19.8 mmol) in toluene (50 mL) at 0°C. was slowly added thionyl bromide (1 mL, 12.9 mmol) and the resultingmixture was stirred at this temperature for 5 min. To this mixture wasslowly added a solution of the alcohol,(±/±)-3,4-Bis(difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinol,from Step 1 (5.6 g, 9.9 mmol) in toluene (50 mL). The mixture wasstirred at room temperature for 1 h and then concentrated to provide thecrude bromide that was used immediately.

To a solution of ethyl 4-pyridylacetate (6.5 g, 39.6 mmol) in THF (200mL) and HMPA (6.8 mL, 39.6 mmol) at room temperature was added potassiumbis(trimethylsilyl)amide (79 mL of a 0.5M solution in toluene, 39.6mmol). The resulting mixture was stirred for 30 min and then a THF (50mL) solution of the crude bromide prepared above was added and thenstirred for 2 h at 25° C. 25% aq. NH₄OAc and ethyl acetate were added,the layers were separated and the aqueous phase was extracted with ethylacetate. The combined organics were washed with brine, dried (Na₂SO₄)and concentrated to give a thick oil. This material was dissolved in amixture of THF/MeOH/water (3:1:1, 300 mL), 2N NaOH (60 mL) was added andthe mixture was heated at 65° C. for 3 h. After cooling to roomtemperature, 6N HCl was slowly added, bringing the pH to approximately6. The mixture was concentrated and partitioned with ethyl acetate and25% aq. NH₄OAc. The aqueous phase was extracted with ethyl acetate andthe combined organics were washed with brine, dried (Na₂SO₄) andconcentrated. Flash chromatography of the residue (silica gel; ethylacetate/hexane 3:2 to 4:1) provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineas an oil (4 g).

Step 3:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridine

To a solution of the protected alcohol,(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl)pyridine,from Step 2 (200 mg, 0.31 mmol) in dichloromethane (3 mL) was added TFA(trifluoroacetic acid) (0.5 mL) and the mixture was stirred at roomtemperature for 15 min. The mixture was concentrated and thenpartitioned with sat. aq. NH₄OAc and ethyl acetate. The aqueous phasewas extracted with ethyl acetate and the combined organics were washedwith brine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; dichloromethane/EtOH 9:1) provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridineas an oil (115 mg).

Step 4:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

A mixture of the(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridinefrom Step 3 (11 5 mg, 0.23 mmol) and MMPP (222 mg, 0.45 mmol) indichloromethane (5 mL) and MeOH (0.5 mL) was heated at 50° C. for 30 minand then additional MMPP (0.5 eq) and MeOH (0.25 mL) was added. Themixture was stirred at 50° C. for 30 min and then at room temperaturefor 15 h. The mixture was concentrated. Flash chromatography of theresidue (silica gel; dichloromethane/MeOH/10% NH₄OH 8:1:1) provided thetitle compound as a colorless foam (117 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.78 (s, 3H), 3.50 (m, 2H), 4.84 (m, 1H),6.5 (d, 1H), 6.95 (t, 1H), 6.96 (t, 1H), 7.21 (d, 2H), 7.33 (m, 2H),7.40(d, 1H, 7.66 (d, 1H), 7.95 (d, 2H).

Example 8

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridineN-oxide

Example 8 was prepared by the following procedure:

Step 1:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridine

To a solution of Intermediate 1 (1.48 g, 3.5 mmol) in dichloromethane(38 mL) at 0° C. was added dropwise PhMgCl (5.2 mL of a 2M solution inTHF, 10.4 mmol). After 30 min, a second aliquot of PhMgCl (2 mL) wasadded. After a further 30 min, sat. aq. NH₄Cl was added and the mixturewas extracted with ethyl acetate (3×). The combined organics were washedwith water, brine, dried (MgSO₄) and concentrated. Chromatography of theresidue (silica gel; dichloromethane/acetone 7:3 to 3:2) provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridineas a colorless oil (1.32 g).

Step 2:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Example 1, Step 4, butsubstituting the(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridinefrom Step 1 (65 mg, 0.13 mmol) for the pyridine from Example 1, Step 3,the(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl}pyridineN-oxide title compound (chromatography silica gel; dichloromethane/EtOH7:3) was obtained as an oil (33 mg).

¹HNMR (500 MHz, acetone-d₆): δ 3.43 (m, 2H), 4.76 (m, 1H), 5.71 (br s,1H), 5.95 (s, 1H), 6.94 (t, 2H), 7.17 (br s, 2H), 7.24-7.49 (m, 4H),7.93 (m, 2H)

Example 9

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridinen-oxide

Example 9 was prepared by the following procedure:

Step 1:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-benzoyl)thiazolyl]ethyl}pyridine

To a solution of oxalyl chloride (0.45 mL, 5.2 mmol) in dichloromethane(20 mL) at −78° C. was added DMSO (0.74 mL, 10 mmol). After 5 min, asolution of the alcohol (1.30 g, 2.58 mmol) from Step 1 of Example 8 indichloromethane (20 mL) was added and the mixture was stirred for 2 h.Triethylamine (3 mL, 22 mmol) was added and after 1.5 h, the mixture waswarmed to room temperature. Water was added and the mixture wasextracted with ethyl acetate (3×). The combined organics were washedwith water, brine, dried (MgSO₄) and concentrated. Flash chromatographyof the residue (silica gel; hexane/ethyl acetate 35:65 to 3:7) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-benzoyl)thiazolyl]ethyl}pyridineas a colorless oil (869 mg).

Step 2:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridine

To a solution of the ketone,(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-benzoyl)thiazolyl]ethyl}pyridine,from the present Step 1 (413 mg, 0.82 mmol) in dichloromethane (20 mL)at −78° C., was added dropwise MeMgBr (0.8 mL of a 3M solution in ether,2.4 mmol). After 15 min, a second aliquot of MeMgBr (0.2 mL) was added.After a further 30 min, 25% aq. NH₄OAc was added and the mixture wasextracted with dichloromethane (3×). The combined organics were washedwith brine, dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel; ethyl acetate/hexane 9:1 to 1:0) provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridine.as a colorless oil (332 mg).

Step 3:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Example 1, Step 4, butsubstituting the(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridinefrom Step 2 (293 mg, 0.57 mmol) for the pyridine from Example 1, Step 3,the title(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)ethyl)thiazolyl]ethyl}pyridineN-oxide compound (chromatography silica gel; dichloromethane/MeOH 9:1)was obtained as a white foam (163 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.92 and 1.93 (s each, 3H), 3.42 (m, 2H),4.72 (m, 1H), 5.70 (br s, 1H), 6.94 (app t, 2H), 7.11-7.37 (m, 8H), 7.49(d, 1H), 7.57 (m, 2H), 7.92 (m, 2H).

Example 10

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 10 was prepared by following the procedures described inExamples 3 and 4, but substituting the ketone from Example 9, Step 1(450 mg, 1.06 mmol) for Intermediate 1. The title compound was obtained(chromatography silica gel; dichloromethane/MeOH 9:1) as a yellow foam(80 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.49 (m, 2H), 4.83 (m, 1H), 6.94 (app t,2H), 7.17-7.35 (m, 4H), 7.40 (m, 4H), 7.69-7.78 (m, 3H), 7.92 (d, 2H).

Example 11

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-phenyl)propyl)thiazolyl]ethyl}pyridineN-oxide

Example 11 was prepared by following the procedures described in Example9, Steps 2 and 3, but substituting EtMgBr (1M in THF) for MeMgBr. Thetitle compound was obtained (chromatography silica gel;dichloromethane/MeOH 9:1) as a foam (80 mg).

¹HNMR (400 MHz, acetone-d₆): δ 0.79 (t, 3H), 2.34 (q, 2H), 3.40 (m, 2H),4.70 (m, 1H), 5.36 (m, 1H), 6.93 (app t, 2H), 7.11-7.35 (m, 8H), 7.51(d, 1H) 7.61 (m, 2H), 7.91 (m, 2H).

Example 12

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-cyclohexylmethanol)thiazolyl]ethyl}pyridine

Example 12 was prepared by the following procedure. To a solution ofIntermediate 1 (740 mg, 1.74 mmol) in dichloromethane (20 mL) at 0° C.was added dropwise cyclohexylmagnesium chloride (2.6 mL of a 2M solutionin ether, 5.2 mmol). After 1 h, sat. aq. NH₄Cl was added and the mixturewas extracted with ethyl acetate (3×). The combined organics were washedwith water, brine, dried (MgSO₄) and concentrated. Flash chromatographyof the residue (silica gel; dichloromethane/MeOH 96:4) provided thetitle compound as a colorless oil (462 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.15 (m, 5H), 1.5-1.8 (m, 6H), 3.45 (m,2H), 4.60 (m, 1H), 4.80 (m, 1H), 5.01 (m, 1H), 6.94 (app t, 2H),7.16-7.50 (m, 6H), 8.35 (m, 2H).

Example 13

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-cyclohexyl-2,2,2-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 13 was prepared by the following procedure:

Step 1:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(cyclohexylcarbonyl)thiazolyl]ethyl}pyridine

Following the procedures described in Example 9, Step 1, butsubstituting the alcohol from Example 12 (446 mg, 0.87 mmol) for thealcohol from Example 8, Step 1,(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(cyclohexylcarbonyl)thiazolyl]ethyl}pyridine(chromatography silica gel; toluene/acetone 4:1 to 3:1) was obtained asan oil (314 mg).

Step 2:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-cyclohexyl-2,2,2-trifluoromethyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Examples 3 and 4, but substitutingthe ketone from the present Step 1 (295 mg, 0.58 mmol) for Intermediate1, the title compound was obtained (chromatography silica gel;dichloromethane/MeOH 9:1) as a foam (97 mg).

¹HNMR (400 MHz, acetone-d₆): δ1.1-1.4 (m, 6H), 1.55-1.95 (m, 4H), 2.3(m, 1H), 3.50 (m, 2H), 4.82 (m, 1H), 6.06 (m, 1H), 6.96 (app t, 2H),7.19 (m, 2H), 7.32 (m, 2H), 7.39 (s, 1H), 7.64 (d, 1H), 7.94 (d, 2H).

Example 14

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-ethyl)phenyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 14 was prepared by the following procedure:

Step 1:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-ethylphenyl)methanol)thiazolyl]ethyl}pyridine

To a solution of Intermediate 1 (426 mg, 1 mmol) in dichloromethane (10mL) at 0° C. was added dropwise 4-ethylphenylmagnesium bromide (7.2 mLof a 0.42M solution in TBF, 3 mmol). After 30 min, a second aliquot of4-ethylphenylmagnesium bromide (2.5 mL) was added. After a further 1 h,the mixture was warmed to room temperature and sat. aq. NH₄Cl was added.The mixture was extracted with ether (2×). The combined organics werewashed with brine (2×), dried (MgSO₄) and concentrated. Chromatographyof the residue (silica gel; dichloromethane/acetone 7:3) provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-ethylphenyl)methanol)thiazolyl]ethyl}pyridineas a yellow syrup (290 mg).

Step 2:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-ethyl)benzoyl)thiazolyl]ethyl}pyridine

A mixture of the alcohol from Step 1 (280 mg, 0.53 mmol), MnO₂ (274 mg,3.2 mmol) and Celite® (500 mg) in dichloromethane (15 mL) was stirred atroom temperature for 24 h. A second aliquot of MnO₂ (137 mg) was addedand stirring continued for a further 3 h. The mixture was filteredthrough Celite®, washing with dichloromethane, and the filtrate wasconcentrated. Flash chromatography of the residue (silica gel;acetone/dichloromethane 3:7) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-ethyl)benzoyl)thiazolyl]ethyl}pyridineas a yellow syrup (236 mg).

Step 3:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-ethyl)phenyl)ethyl)thiazolyl]ethyl}pyridine

To a solution of the ketone from Step 2 (236 mg, 0.45 mmol) indichloromethane (5 mL) at 0° C. was added dropwise MeMgCl (0.52 mL of a3M solution in THF, 1.56 mmol). After 15 min, sat. aq. NH₄Cl and ethylacetate were added. The aqueous phase was extracted with ethyl acetate(3×). The combined organics were dried (MgSO₄) and concentrated. Flashchromatography of the residue (silica gel; dichloromethane/acetone 7:3)provided(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-ethyl)phenyl)ethyl)thiazolyl]ethyl}pyridineas a yellow syrup (228 mg).

Step 4:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-ethyl)phenyl)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Example 1, Step 4, butsubstituting the pyridine from the present Step 3 (198 mg, 0.36 mmol)for the pyridine from Example 1, Step 3, the title compound(chromatography silica gel; dichloromethane/MeOH 92.5:7.5) was obtainedas a white foam (169 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.16 (m, 3H), 1.91 and 1.92 (s each, 3H),2.57 (m, 2H), 3.42 (m, 2H), 4.73 (m, 1H), 5.54 (m, 1H), 6.94 (app t, 2H)7.11-7.18 (m, 4H), 7.24-7.36 (m, 3H), 7.45-7.50 (m, 3H), 7.91 (m, 2H).

Example 15

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-ethyl)phenyl-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 15 was prepared by following the procedures described inExamples 3 and 4, but substituting the ketone from Example 14, Step 2(210 mg, 0.4 mmol) for Intermediate 1. The title compound was obtained(chromatography silica gel; dichloromethane/MeOH 9:1) as a white foam(117 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.20 (m, 3H), 2.63 (m, 2H), 3.48 (m, 2H),4.82 (m, 1H), 6.92 (app t, 2H), 7.10-7.35 (m, 7H), 7.40 (s, 1H),7.61-7.74 (m, 3H), 7.93 (d, 2H).

Example 16

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-fluoro)phenyl)ethyl)thiazolyl]ethyl]pyridineN-oxide

Example 16 was prepared by following the procedures described inExamples 14, but substituting 4-fluorophenylmagnesium bromide for4-ethylphenylmagnesium bromide. The title compound was obtained(chromatography silica gel; dichloromethane/MeOH 9:1) as a white foam(100 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.91 (m, 3H), 3.46 (m, 2H), 4.73 (m, 1H),5.78 (m, 1H), 6.92 (app t, 2H), 7.05 (m, 2H), 7.17 (m, 2H), 7.25-7.38(m, 3H), 7.51 (d, 1H), 7.60 (m, 2H), 7.92 (m, 2H).

Example 17

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-11(4-fluoro)phenyl-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 17 was prepared by the following procedure:

Step 1:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-fluoro)benzoyl)thiazolyl]ethyl}pyridine

Following the procedures described in Examples 14, Steps 1 and 2, butsubstituting 4-fluorophenylmagnesium bromide for 4-ethylphenylmagnesiumbromide,(±)4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(4-fluoro)benzoyl)thiazolyl]ethyl}pyridinewas obtained (chromatography silica gel; hexane/ethyl acetate 2:3 to3:7) as a white foam (443 mg).

Step 2:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(4-fluoro)phenyl-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Examples 3 and 4, but substitutingthe ketone from the present Step 1 (300 mg, 0.58 mmol) for Intermediate1, the title compound was obtained (chromatography silica gel;dichloromethane/EtOH 9:1) as a foam (100 mg).

¹HNMR (400 MHz, acetone-d₆): δ 3.49 (m, 2H), 4.83 (m, 1H), 6.94 (app t,2H), 7.12-7.23 (m, 4H), 7.30 (m, 2H), 7.40 (m, 2H), 7.71 (m, 1H), 7.82(m, 2H), 7.93 (d, 2H).

Example 18

(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(5-bromopyridin-2-yl)-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 18 was prepared by the following procedure:

Step 1:(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(5-bromopyridin-2-yl)methanol)thiazolyl]ethyl}pyridine

To a solution/suspension of 2,5-dibromopyridine (427 mg, 1.8 mmol) intoluene (20 mL) at −78° C. was slowly added n-BuLi (0.72 mL of a 2.3Msolution in hexane, 1.65 mmol) and the resulting mixture was stirred atthis temperature for 3.5 h. To this mixture was added a solution ofIntermediate 1 (639 mg, 1.5 mmol) in toluene (5 mL). After 75 min, sat.aq. NH₄Cl was added and the mixture was warmed to room temperature. Themixture was extracted with ethyl acetate (2×) and the combined organicswere washed with water (3×), dried (MgSO₄), concentrated and used assuch in the subsequent reaction below.

Step 2:(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(5-bromopyridin-2-yl)keto)thiazolyl]ethyl}pyridine

A mixture of the alcohol from the present Step 1, MnO₂ (1.96 g, 22.5mmol) and Celite® (3 g) in dichloromethane (30 mL) was stirred at roomtemperature for 24 h. The mixture was filtered through Celite®, washingwith dichloromethane, and the filtrate was concentrated. Flashchromatography of the residue (silica gel; ethyl acetate) provided(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(5-bromopyridin-2-yl)keto)thiazolyl]ethyl}pyridineas an oil (247 mg).

Step 3:(±/±)-4-[2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(5-bromopyridin-2-yl)-2,2.2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Examples 3 and 4, but substitutingthe ketone from the present Step 2 (235 mg, 0.40 mmol) for Intermediate1, the title compound was obtained (chromatography silica gel;dichloromethane/EtOH 9:1) as a yellow foam (32 mg).

¹HNMR (400 Mz, acetone-d₆): δ 3.40-3.57 (m, 2H), 4.84 (m, 1H), 6.94 (appt, 2H), 7.16-7.34 (m, 5H), 7.39 (s, 1H), 7.76 (d, 1H), 7.91-7.95 (m, 2H)8.13 (m, 1H), 8.21-8.25 (m, 1H), 8.77 (s, 1H).

Example 19

(±/±)-4-1{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(1-hydroxy-1-(6-bromopyridin-3-yl)-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Example 19 was prepared by the following procedure:

Step 1:(±/±)-4-{2-[{3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(6-bromopyridin-3-yl)methanol)thiazolyl]ethyl}pyridine

To a solution/suspension of 2,5-dibromopyridine (1.66 g, 7 mmol) inether (50 mL) at −78° C. was slowly added n-BuLi (2.6 mL of a 2.3Msolution in hexane, 6 mmol) and the resulting mixture was stirred atthis temperature for 1.5 h. To this mixture was added a solution ofIntermediate I (2.13 g, 5 mmol) in ether (20 mL). The mixture wasstirred at −78° C. for 2 h and then warmed to O° C. After 3.5 h, sat.aq. NH₄Cl (75 mL) was added and the mixture was warmed to roomtemperature. The mixture was partitioned with ethyl acetate and waterand the organic phase was dried (MgSO₄), concentrated and used as suchin the subsequent reaction.

Step 2: (±/±)-4-1 2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-1-(6-bromopyridin-3-yl)-2,2,2-trifluoro)ethyl)thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Example 18, Steps 2 and 3, butsubstituting the alcohol obtained from the present Step 1 for thealcohol from Example 18, Step 1, the title compound was obtained(chromatography silica gel; dichloromethane/MeOH 9:1) as a white foam(374 mg).

¹HNMR (400 Mz, acetone-d₆): δ 3.41-3.56 (m, 2H), 4.87 (m, 1H), 6.95 (appt, 2H), 7.20 (m, 2H), 7.28-7.35 (m, 2H), 7.40 (s, 1H), 7.69 (m, 1H),7.75 (s, 1H), 7.82 (br s, 1H), 7.92 (m, 2H), 8.12 (m, 1H), 8.76 (s, 1H).

Example 20

(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy)cyclobutyl]thiazolyl}ethyl}pyridineN-oxide

Example 20 was prepared by following the procedures described in Example1, but substituting Thiazole 4 for Thiazole 1. The title compound wasobtained (chromatography silica gel; dichloromethane/MeOH 92:8) as awhite solid (164 mg, m.p. 151-153° C.).

¹HNMR (400 MHz, acetone-d₆): δ 1.89 (m, 2H), 2.22 (m, 2H), 2.55 (m, 2H),3.47 (m, 2H), 4.78 (m, 1H), 5.42 (br s, 1H), 6.95 (app t, 1H), 6.96 (t,1H), 7.21 (m, 2H), 7.30 (m, 2H), 7.38 (s, 1H), 7.53 (s, 1H), 7.95 (d,2H).

Example 21

(±)-4-1{2-[3,4-Bis(difluoromethoxy)phenyl]-2-1{5-[2-(11-hydroxy)cyclohexyl]thiazolyl}ethyl}pyridineN-oxide

Example 21 was prepared by following the procedures described in Example1, but substituting Thiazole 5 for Thiazole 1. The title compound wasobtained (chromatography silica gel; dichloromethane/MeOH 9:1) as a foam(1144 mg).

¹HNMR (400MHz, acetone-d₆): δ 1.30 (m, 1H), 1.50-1.80 (m, 711), 1.90 (m,2H), 3.44 (m, 2H), 4.75 (m, 2H), 6.95 (app t, 2H), 7.20 (m, 2H), 7.29(m, 2H), 7.37 (s, 1H), 7.48 (s, 1H), 7.94 (d, 2H).

Example 22

(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 22 was prepared by the following procedure:

Step 1:(±)-(3-Cyclobutyloxy-4-difluoromethoxy)phenyl-5-{2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinol

To a solution of Thiazole 1 (1.0 g, 3.66 mmol) in anhydrous ether (10mL) at −78° C. was added n-BuLi (2.3 mL of a 1.6M solution in hexane,3.66 mmol). After 40 min, a solution of3-cyclobutyloxy-4-difluoromethoxybenzaldehyde (886 mg, 3.66 mmol) inanhydrous ether (2 mL) was added. The mixture was stirred at −78° C. for35 min and then 25% aq. NH₄OAc was added. The mixture was allowed towarm to room temperature and then partitioned with ethyl acetate andwater. The aqueous phase was extracted with ethyl acetate and thecombined organics were washed with brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel;hexane/ethyl acetate 65:35) provided(±)-(3-Cyclobutyloxy-4-difluoromethoxy)phenyl-5-{2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl}thiazolylcarbinolas an amber oil (1.2 g).

Step 2:(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridine

To a solution of pyridine (0.47 mL, 5.82 mmol) in toluene (2 mL) at roomtemperature was slowly added thionyl chloride (0.20 mL, 2.79 mmol) andthe resulting mixture was stirred for 10 min. To this mixture was slowlyadded a solution of the alcohol from the present Step 1 (1.2 g, 2.33mmol) in toluene (2 mL). The mixture was stirred for 25 min to give aprecipitate. The liquid was decanted and the residual solid washed withtoluene. The combined organics were concentrated to provide the crudechloride as an amber oil that was used immediately.

To a solution of ethyl 4-pyridylacetate (1.15 g, 7 mmol) in THF (10 mL)and HMPA (1.21 mL, 7 mmol) at room temperature was added potassiumbis(trimethylsilyl)amide (14 mL of a 0.5M solution in toluene, 7 mmol).The resulting mixture was stirred for 30 min and then a THF (5 mL)solution of the crude chloride prepared above was added and then stirredfor 17 h at 25° C. Then, 25% aq. NH₄OAc was added, the layers wereseparated and the aqueous phase was extracted with ethyl acetate. Thecombined organics were washed successively with brine, dried (MgSO₄) andconcentrated to give a thick orange oil. This material was dissolved ina mixture of THF/MeOH/water (3:1:1, 25 mL), LiOH (557 mg) was added andthe mixture was heated at 70° C. for 1 h. After cooling to roomtemperature, 1N HCl (25 mL) was slowly added. The mixture was extractedthree times with ethyl acetate and the combined organics were washedwith brine, dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel; ethyl acetate/hexane 3:1) provided(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineas an orange oil (892 mg).

Step 3:(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineN-oxide

A mixture of the(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridinefrom Step 2 (892 mg, 1.51 mmol) and MMPP (747 mg, 1.51 mmol) indichloromethane (9 mL) and MeOH (1 mL) was stirred at room temperaturefor 16 h. The mixture was partitioned with ethyl acetate and sat. aq.NaHCO₃. The aqueous phase was extracted with ethyl acetate and thecombined organics were washed with brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel;dichloromethane/MeOH 9:1) provided(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineN-oxide as a pale yellow foam (782 mg).

Step 4: (±)-4-{2-r(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-15-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridine N-oxide

To a solution of the protected alcohol,(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridineN-oxide, from Step 3 (782 mg, 1.29 mmol) in dichloromethane (10 mL) at0° C. was added TFA (1 mL) and the mixture was stirred at 0° C. for 20min. The mixture was warmed to room temperature and then stirred for anadditional 5 h. 25% aq. NH₄OAc was added and the mixture was extractedwith ethyl acetate. The organics were washed with brine, dried (MgSO₄)and concentrated. Flash chromatography of the residue (silica gel;dichloromethane/MeOH 9:1) provided the title product as an off whitesolid (520 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.51 (s, 6H), 1.67 (m, 1H), 1.81 (m, 1H),2.0-2.2 (m, 2H), 2.35-2.50 (m, 2H), 3.42 (m, 2H), 4.66 (t, 1H), 4.74 (m,1H), 4.91 (br s, 1H), 6.84 (t, 1H), 6.92 (m, 1H), 6.97 (m, 1H), 7.08 (d,1H), 7.18 (d, 2H), 7.48 (s, 1H), 7.97 (d, 2H).

Example 23

Chiral4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 23 was prepared by the following procedure:

Step 1: Resolution of(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridine

A solution of(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[5-(2-(1-methyl-1-[(2-trimethylsilylethoxy)methoxy]ethyl)thiazolyl]ethyl}pyridine(Example 22, Step 2; 2.3 g) in isopropanol/hexane (30 mL, 1:4) wasinjected (5×6 mL) onto a Chiralpak® AD preparative (5 cm×50 cm) HPLCcolumn (eluting with hexane/isopropanol 96:4 at 75 ml/min with UVdetection at 280 nm). The enantiomers were separated with the fastereluting enantiomer having a retention time of 46 min (Enantiomer 1) andthe slower eluting enantiomer (Enantiomer 2) having a retention time of5 1 min. The eluants were concentrated to provide the enantiomers asoff-white gums: Enantiomer 1 (76 1 mg) and Enantiomer 2 (547 mg).

Step 2: Chiral4-{2-r(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl]ethyl}pyridineN-oxide

Following the procedures described in Example 22, Steps 3 and 4, butsubstituting chiral pyridine from the present Step 1 (Enantiomer 1; 750mg, 1.27 mmol) for the racemic pyridine from Example 22, Step 2, thetitle compound was obtained (chromatography silica gel; chloroform/EtOH9:1 to 4:1) as a white foam (473 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.52 (s, 6H), 1.68 (m, 1H), 1.81 (m, 1H),2.0-2.2 (m, 2H), 2.38-2.50 (m, 2H), 3.36-3.47 (m, 2H), 4.66 (t, 1H) 4.75(m, 1H), 4.90 (br s, 1H), 6.83 (t, 1H), 6.92 (m, 1H), 6.96 (m, 1H), 7.08(d, 1H), 7.17 (d, 2H), 7.47 (s, 1H), 7.97 (d, 2H).

Example 24

(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]triazolyl}ethyl}pyridine

Example 24 was prepared by following the procedures described in Example5, but substituting 3-cyclobutyloxy-4-difloromethoxybenzaldehyde for3,4-bis(difluoromethoxy)benzaldehyde, the title compound (chromatographysilica gel; toluene/acetone 7:3) was obtained as a foam (277 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.66 (m, 1H), 1.80 (m, 1H), 2.0-2.2 (m,2H), 2.30-2.50 (m, 2H), 3.40-3.53 (m, 2H), 4.70 (m, 1H), 4.78 (t, 1H),6.83 (t, 1H), 6.94 (m, 2H), 7.06 (d, 1H), 7.16 (d, 2H), 7.68 (s, 1H),8.37 (br s, 2H).

Example 25

(±)-4-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 25 was prepared by following the procedures described in Example6, but substituting Example 24 (203 mg, 0.35 mmol) for Example 5. Thetitle compound (chromatography silica gel; dichloromethane/MeOH 93:7)was obtained as a white foam (100 mg).

¹HNMR (400 MHz, acetone-d₆): δ 1.67 (m, 1H), 1.81 (m, 1H), 2.0-2.2 (m,2H), 2.30-2.50 (m, 2H), 3.45-3.59 (m, 2H), 4.75 (m, 1H), 4.81 (t, 1H),6.85 (t, 1H), 6.94-7.0 (m, 2H), 7.10 (d, 1H), 7.19 (d, 2H), 7.81 (s,1H), 7.97 (br d, 2H), 8.45 (br s, 1H).

Examples 26 and 27

Chiral3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]Thiazolyl}ethyl}pyridine

Examples 26 and 27 were prepared by the following precedure:

Step 1:(±)-3-[2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl]ethyl}pyridine

To a solution of pyridine (1.8 mL, 22.2 mmol) in toluene (50 mL) at 0°C. was slowly added thionyl chloride (0.78 mL, 10.7 mmol) and theresulting mixture was stirred at room temperature for 15 min. To thismixture was slowly added a solution of the alcohol from Example 22, Step1 (4.6 g, 8.9 mmol), in toluene (25 mL). The mixture was stirred for 20min to give a precipitate. The mixture was filtered and the residualsolid washed with toluene. The combined organics were concentrated toprovide the crude chloride as an amber oil that was used immediately.

To a solution of ethyl 3-pyridylacetate (4.4 g, 26.7 mmol) in THF (10mL) and HMPA (4.6 mL, 26.7 mmol) at room temperature was added potassiumbis(trimethylsilyl)amide (53.4 mL of a 0.5M solution in toluene, 7mmol). The resulting mixture was stirred for 20 min and then a THF(201L) solution of the crude chloride prepared above was added and thenstirred for 17 h at 25° C. The mixture was poured into 25% aq. NH₄OAc,the layers were separated and the aqueous phase was extracted with ethylacetate (3×). The combined organics were washed successively with water(3×), dried (MgSO₄) and concentrated. Flash chromatography of theresidue (silica gel; ethyl acetate/hexane 1:1 to 3:2) provided theesters as a yellow oil (2.5 g).

This material (2.5 g, 3.8 mmol) was dissolved in a mixture ofTBF/MeOH/water (3:1:1, 30 mL), 2N LiOH (5.7 mL, 11.4 mmol) was added andthe mixture was heated at 70° C. for 30 min and then stirred at roomtemperature for 15 h. 4N HCl (25 mL) was slowly added, bringing themixture to pH 5. The mixture was concentrated and then extracted threetimes with ethyl acetate. The combined organics were washed with water(3×), dried (MgSO₄) and concentrated to give the acid (2.1 g). The acidwas dissolved in DMSO (10 ML) and heated at 150° C. for 7 h and thenstirred at room temperature for 15 h. Water (50 mL) and brine (5 mL)were added and the mixture was extracted with dichloromethane (3×). Thecombined organics were washed with water (3×), dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel; ethylacetate/EtOH 1:0 to 9:1) provided the title product as an oil (855 mg).

Step 2: Resolution of(±)-3-12-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl]ethyl]pyridine

A solution of the material from the present Step 1 (855 mg) inEtOH/hexane (5 mL, 2:3) was injected onto a Chiralpak® AD preparative (5cm×50 cm) HPLC column (eluting with hexane/EtOH 85:15 at 80 mL/min withUV detection at 0.280 nm). The enantiomers were separated with thefaster eluting enantiomer having a retention time of 25 min(Enantiomer 1) and the slower eluting enantiomer (Enantiomer 2) having aretention time of 34 min. The eluants were concentrated to provide theenantiomers as white foams: Enantiomer 1 (Example 26, 400 mg) andEnantiomer 2 (Example 27, 385 mg).

¹HNMR (500 MHz, acetone-d₆) for both enantiomers: δ 1.52 (s, 6H), 1.67(m, 1H), 1.81 (m, 1H), 2.0-2.2 (m, 2H), 2.34-2.50 (m, 2H), 3.34-3.49 (m,2H), 4.63 (t, 1H), 4.73 (m, 1H), 4.86 (s, 1H), 6.82 (t, 1H), 6.90-6.95(m, 2H), 7.07 (d, 1H), 7.18 (m, 1H), 7.46 (s, 1H), 7.55 (d, 1H), 8.42(m, 1H), 8.47 (s, 1H).

Example 28

Chiral3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 28 was prepared by the following procedure. A mixture of Example26 (Enantiomer 1; 400 mg, 0.87 mmol) and MMPP (430 mg, 0.87 mmol) indichloromethane (9 mL) and MeOH (0.9 mL) was stirred at room temperaturefor 16 h. The mixture was partitioned with dichloromethane and sat. aq.NaHCO₃. The aqueous phase was extracted with dichloromethane and thecombined organics were washed with brine, dried (MgSO₄) andconcentrated. Flash chromatography of the residue (silica gel;dichloromethane/EtOH 9:1 to 4:1) provided the title compound as a whitefoam (280 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.52 (s, 6H), 1.66 (m, 1H), 1.81 (m, 1H),2.0-2.2 (m, 2H), 2.37-2.50 (m, 2H), 3.33-3.47 (m, 2H), 4.69 (t, 1H 4.75(m, 1H), 4.93 (br s, 1H), 6.82 (t, 1H), 6.93-7.00 (m, 2H), 7.09 (t, 2H),7.20 (t, 1H), 7.49 (s, 1H), 7.92 (d, 1H), 8.02 (s, 1H).

Example 29

Chiral3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 29 was prepared by following the procedures described in Example28, but substituting Example 27 (Enantiomer 2; 385 mg, 0.84 mmol) forExample 26. The title compound (chromatography silica gel;dichloromethane/EtOH 9:1 to 4:1) was obtained as a white foam (310 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.52 (s, 6H), 1.66 (m, 1H), 1.81 (m, 1H),2.0-2.2 (m, 2H), 2.37-2.50 (m, 2H), 3.33-3.47 (m, 2H), 4.69 (t, 1H),4.75 (m, 1H), 4.93 (br s, 1H), 6.82 (t, 1H), 6.93-7.00 (m, 2H), 7.09 (t,2H), 7.20 (t, 1H), 7.49 (s, 1H), 7.92 (d, 1H), 8.02 (s, 1H).

Examples 30 and 31

Chiral3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Examples 30 and 31 were prepared by the following procedure:

Step 1:(±)-(3-Cyclobutyloxy-4-difluoromethoxy)phenyl-5-[2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl]thiazolylcarbinol

To a solution n-BuLi (8.5 mL of a 1.6M solution in hexane, 13.6 mmol) inanhydrous ether (20 mL) at −78° C. was added a solution of Thiazole 2(5.17 g, 13.55 mmol) in anhydrous ether (10 mL). After 1.5 h, thismixture was added to a solution of3-cyclobutyloxy-4-difluoromethoxybenzaldehyde (2.17 g, 8.97 mmol) inanhydrous ether (30 mL) at −78° C. The mixture was stirred at −78° C.for 2 h and then sat. aq. NH₄Cl was added. The mixture was extractedwith ethyl acetate and the organics were washed with brine, dried(Na₂SO₄) and concentrated. Flash chromatography of the residue (silicagel; hexane/ethyl acetate 95:5 to 7:3) provided(±)-(3-Cyclobutyloxy-4-difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazolylcarbinolas a yellow oil (4.99 g).

Step 2: (±)-3-12-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

To a solution of pyridine (2 mL, 26.7 mmol) in toluene (5 mL) at 0° C.was slowly added thionyl bromide (1 mL, 12.9 mmol) and the resultingmixture was stirred for 10 min. To this mixture was slowly added asolution of the alcohol from the present Step 1 (4.99 g, 8.0 mmol) intoluene (15 mL). The mixture was warmed to room temperature and stirredfor 45 min to give a precipitate. The mixture was added directly to asilica gel column and eluted with hexane/ethyl acetate (4:1) to providethe crude bromide as a pale yellow oil (3.67 g) that was usedimmediately.

To a solution of ethyl 3-pyridylacetate N-oxide (2.4 g, 13.25 mmol) inTHF (80 mL) and HMPA (2.4 mL, 13.8 mmol) at 0° C. was added potassiumbis(trimethylsilyl)amide (27 mL of a 0.5M solution in toluene, 13.5mmol). The resulting mixture was warmed to room temperature and stirredfor 1.5 h. The mixture was re-cooled to 0° C. and then a THF (10 mL)solution of the crude bromide prepared above (2.97 g, 4.33 mmol) wasadded. After stirring for 17 h at 25° C., the mixture was poured intosat. aq. NH₄Cl, the layers were separated and the aqueous phase wasextracted with ethyl acetate. The combined organics were washed withbrine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; dichloromethane/EtOH 98:2 to 95:5) provided theesters as a yellow oil (3.2 g).

This material (3.2 g, 3.7 mmol) was dissolved in a mixture ofTHF/MeOH/water (3:1:1, 35 mL), 1.7N LiOH (7 mL, 11.9 mmol) was added andthe mixture was heated at 60° C. for 5 h. A second aliquot of 1.7N LiOH(7 mL) was added and heating was continued for a further 4 h. Themixture was cooled to room temperature and then 2N HCl (14 mL) wasslowly added. The mixture was concentrated and partitioned between ethylacetate and water. The aqueous phase was extracted with ethyl acetateand the combined organics were washed with brine, dried (Na₂SO₄) andconcentrated to give the acid (2.64 g). The acid was dissolved in DMSO(20 mL) and heated at 110-130° C. for 4.5 h and then stirred at roomtemperature for 15 h. Water (200 mL) was added and the mixture wasextracted with dichloromethane (3×). The combined organics were washedwith brine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; dichloromethane/MeOH/10% aq. NH₄OH 90:5:5) provided(±)-3-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide as a white foam (1.4 g).

Step 3: Resolution of(±)-3-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

A solution of the material from the present Step 2 (1.4 g) inEtOH/hexane (20 mL, 3:7) was injected (4×5 mL) onto a Chiralpak® ADpreparative (5 cm×50 cm) HPLC column (eluting with hexane/EtOH 9:1 at60-80 mL/min with UV detection at 270 nm). The enantiomers wereseparated with the faster eluting enantiomer having a retention time of˜16 min (Enantiomer 1, Example 30) and the slower eluting enantiomer(Enantiomer 2, Example 31) having a retention time of 19 min. Theeluants were concentrated to provide the enantiomers as white foams:Enantiomer 1 (579 mg) and Enantiomer 2 (132 mg).

¹HNMR (500 MHz, acetone-d₆) for each enantiomer: δ 1.65 (m, 1H), 1.81(m, 1H), 2.0-2.2 (m, 2H), 2.35-2.50 (m, 2H), 3.43-3.57 (m, 2H), 4.76 (m,1H), 4.87 (t, 1H), 6.85 (t, 1H), 6.96-7.02 (m, 2H), 7.10 (t, 2H), 7.22(t, 1H), 7.35 (s, 1H), 7.94 (d, 1H), 8.06 (s, 1H), 8.28 (br s, 1H).

Example 32

(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 32 was prepared by the following procedure:

Step 1:(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl]thiazolyl}ethyl}pyridine

To a solution of diisopropylamine (0.14 mL, 1 mmol) in THF (2 mL) at 0°C. was added n-BuLi (0.62 mL of a 1.6M solution in hexane, 0.99 mmol).After 45 min, the resulting mixture was cooled to −78° C. and ethyl2-pyridylacetate (0.15 mL, 0.98 mmol) was added. The mixture stirred for1 h and then a THF (4 mL) solution of the bromide prepared in Example30, Step 2 (0.22 g, 0.33 mmol) was added. After stirring for 17 h at 25°C., the mixture was poured into 25% aq. NH₄OAc. The aqueous phase wasextracted with ethyl acetate and the organics were washed with brine,dried (Na₂SO₄) and concentrated.

This material was dissolved in a mixture of THF/MeOH/water (3:1:1, 10mL), 1.7 N LiOH (211L, 3.4 mmol) was added and the mixture was heated at60° C. for 2.5 h. The mixture was cooled to room temperature and then 2NHCl (2 mL) was slowly added. The mixture was concentrated andpartitioned between ethyl acetate and 25% aq. NH₄₀Ac. The aqueous phasewas extracted with ethyl acetate and the combined organics were washedwith brine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; hexane/ethyl acetate 7:3) provided the protectedalcohol,(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl]thiazolyl}ethyl}pyridine,as an oil (169 mg).

Step 2:(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridine

A mixture of the protected alcohol from the present Step 1 (169 mg, 0.24mmol) and TBAF (2.5 mL of a 1M solution in THF, 2.5 mmol) in THF (3 mL)was heated at 60° C. for 17 h. 25% aq. NH₄OAc was added, the mixture wasextracted with ethyl acetate and the combined organics were washed withbrine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; hexane/ethyl acetate 1:1) provided(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineas an oil (107 mg).

Step 3:(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

A mixture of(±)-2-{2-[(3-Cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridinefrom the present Step 2 (107 mg, 0.19 mmol) and MMPP (185 mg, 0.37 mmol)in dichloromethane (5 mL) and MeOH (0.5 mL) was stirred at roomtemperature for 2 h. A second aliquot of MMPP (185 mg) was added and themixture was stirred for 48 h. The mixture was filtered through Celite®and concentrated. Flash chromatography of the residue (silica gel;dichloromethane/MeOH/10% aq. NH₄₀H 95:2.5:2.5), followed by a secondchromatography of the mixed fractions (silica gel; ethyl acetate/EtOH95:5) provided the title compound as a white foam (26 mg).

¹HNMR (500 MHz, acetone-d₆): δ 1.65 (m, 1H), 1.80 (m, 1H), 1.95-2.18 (m,2H), 2.32-2.48 (m, 2H), 3.60 (m, 1H), 3.75 (m, 1H), 4.63 (m, 1H), 5.28(t, 1H), 6.83 (t, 1H), 6.90-7.97 (m, 2H), 7.09 (d, 2H), 7.15 (m, 2H),7.29 (m, 1H), 7.80 (s, 1H), 8.23 (d, 1H), 8.70 (br s, 1H).

Example 33

(±)-4-{2-[(3-Cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-methyl)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 33 was prepared by following the procedures described in Example22, but substituting 3-cyclopropyloxy-4-difluoromethoxybenzaldehyde for3-cyclobutyloxy-4-difluoromethoxybenzaldehyde. The title compound(chromatography silica gel; dichloromethane/EtOH 7:3) was obtained as awhite foam (126 mg).

¹HNMR (400 MHz, acetone-d₆): δ 0.60-0.85 (m, 4H), 1.52 (s, 6H),3.36-3.50 (m, 2H), 3.88 (m, 1H), 4.69 (t, 1H), 4.95 (s, 1H), 6.76 (t,1H), 6.95 (m, 1H), 7.07 (d, 1H), 7.18 (d, 2H), 7.41 (m, 1H), 7.48 (s,1H), 7.96 (d, 2H).

Example 34

(±)-3-{2-[(3-Cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Example 34 was prepared by the following procedure:

Step 1:(±)-(3-Cyclopropyloxy-4-difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazolylcarbinol

To a solution n-BuLi (13 mL of a 1.6M solution in hexane, 20.8 mmol) inanhydrous ether (400 mL) at −78° C. was added a solution of Thiazole 2(8.07 g, 21.2 mmol) in anhydrous ether (25 mL). After 1.5 h, thismixture was added to a solution of3-cyclopropyloxy-4-difluoromethoxybenzaldehyde (3.03 g, 13.3 mmol) inanhydrous ether (30 mL) at −78° C. The mixture was stirred at −78° C.for 1.75 h and then sat. aq. NH₄Cl was added. The mixture was extractedwith ethyl acetate and the organics were washed with brine, dried(Na₂SO₄) and concentrated. Flash chromatography of the residue (silicagel; hexane/ethyl acetate 9:1 to 7:3) provided the alcohol,(±)-(3-Cyclopropyloxy-4-difluoromethoxy)phenyl-5-{2-(1-trifluoromethyl-1-[(2-trimethylsilylethoxy)methoxy]-2,2,2-trifluoroethyl}thiazolylcarbinol,as a yellow oil (7.05 g).

Step 2:(±)-3-{2-[(3-Cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

To a solution of pyridine (1.6 mL, 19.8 mmol) in toluene (5 mL) at 0° C.was slowly added thionyl bromide (0.84 mL, 10.8 mmol) and the resultingmixture was stirred for 5 min. To this mixture was slowly added asolution of the alcohol from the present Step 1 (4.38 g, 7.2 mmol) intoluene (10 mL). The mixture was warmed to room temperature and stirredfor 45 min. The mixture was added directly to a silica gel column andeluted with hexane/ethyl acetate (95:5 to 7:3) to provide the crudebromide as a yellow oil (2.59 g) that was used immediately.

To a suspension of ethyl 3-pyridylacetate N-oxide (2 g, 11.0 mmol) inTHF (60 mL) and HMPA (2 mL, 11.5 mmol) at 0° C. was added potassiumbis(trimethylsilyl)amide (22 mL of a 0.5M solution in toluene, 11.0mmol). The resulting mixture was warmed to room temperature and stirredfor 1.5 h. The mixture was re-cooled to 0° C. and then a THF (10 mL)solution of the crude bromide prepared above (2.37 g, 3.5 mmol) wasadded. After stirring for 17 h at 25° C., the mixture was poured intosat. aq. NH₄Cl, the layers were separated and the aqueous phase wasextracted with ethyl acetate. The combined organics were washed withbrine, dried (Na₂SO₄) and concentrated. Flash chromatography of theresidue (silica gel; dichloromethane/EtOH 98:2 to 95:5) provided theesters as a white foam (2.35 g).

This material (2.35 g, 3.5 mmol) was dissolved in a mixture ofTHF/MeOH/water (3:1:1, 33 mL). Next, 1.7N LiOH (6.5 mL, 11.1 mmol) wasadded and the resulting mixture was heated at 60° C. for 2.5 h. Themixture was cooled to room temperature and then 2N HCl (6.5 mL) wasslowly added. The mixture was concentrated and partitioned between ethylacetate and water. The aqueous phase was extracted with ethyl acetateand the combined organics were washed with brine, dried (Na₂SO₄) andconcentrated to give a yellow solid (2.4 g). This material was dissolvedin DMSO (30 mL) and heated at 130° C. for 2 h. Water (300 mL) was addedand the mixture was extracted with dichloromethane (3×). The combinedorganics were washed with brine, dried (Na₂SO₄) and concentrated. Flashchromatography of the residue (silica gel; dichloromethane/MeOH/10% aq.NH₄OH 90:2.5:2.5 to 90:5:5) provided the title product as a white foam(1.66 g).

¹HNMR (500 MHz, acetone-d₆): δ 0.60-0.88 (m, 4H), 3.48 (m, 1H), 3.58 (m,1H), 3.90 (m, 1H), 4.90 (t, 1H), 6.79 (t, 1H), 7.01 (m, 1H), 7.12 (m,2H) 7.22 (m, 1H), 7.49 (s, 1H), 7.86 (s, 1H), 7.95 (d, 1H), 8.09 (s,1H), 8.33 (br s, 1H).

Examples 35 and 36

Chiral3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl}ethyl}pyridineN-oxide

Examples 35 and 36 were prepared by the following procedure. A solutionof the material from Example 34 (1.66 g) in EtOH/hexane (20 mL, 3:7) wasinjected (4×5 mL) onto a Chiralpak® AD preparative (5 cm×50 cm) HPLCcolumn (eluting with hexane/EtOH 9:1 at 80 mL/min with UV detection at270 nm). The enantiomers were separated with the faster elutingenantiomer having a retention time of 16 min (Enantiomer 1, Example 35)and the slower eluting enantiomer (Enantiomer 2, Example 36) having aretention time of 19 min. The eluants were concentrated to provide theenantiomers as white foams: Enantiomer 1 (652 mg) and Enantiomer 2 (134mg).

¹HNMR (500 MHz, acetone-d₆) for each: δ 0.60-0.88 (m, 4H), 3.48 (m, 1H),3.58 (m, 1H), 3.90 (m, 1H), 4.90 (t, 1H), 6.79 (t, 1H), 7.01 (m, 1H),7.12 (m, 2H), 7.22 (m, 1H), 7.49 (s, 1H), 7.86 (s, 1H), 7.95 (d, 1H),8.09 (s, 1H), 8.33 (br s, 1H).

Other variations or modifications, which will be obvious to thoseskilled in the art, are within the scope and teachings of thisinvention. This invention is not to be limited except as set forth inthe following claims.

1. A pharmaceutical composition comprising a Leukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor, or an M2/M3 antagonist; a compound represented by Formula (1):

 or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with 1-4 independent halogen; R² is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with 1-4 independent halogen; R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C₁₋₆alkyl; R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4 independent halogen; R^(P) is H, halogen, nitrile, or a C¹⁻⁶alkyl group, said alkyl optionally substituted with 1-4 independent halogen; n is 0 or 1; and when R³ and R⁴ are connected to each other through X, then R³ and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl; and a pharmaceutically acceptable carrier.
 2. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock, laminitis in horses, colic in horses, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection, graft versus host disease, hypersecretion of gastric acid, bacterial, fungal induced sepsis, viral induced sepsis, fungal induced septic shock, viral induced septic shook, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth, or cancerous invasion of normal tissues, osteoporosis, or bone loss, comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with 1-4 independent halogen; R² is C₁₋₆alkyl or C₃₋₆cycloalkyl, optionally substituted with 1-4 independent halogen; R³ is C₁₋₄alkyl, C₃₋₆cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C₁₋₆alkyl; R⁴ is H or C₁₋₄alkyl, said alkyl optionally substituted with 1-4 independent halogen; R^(P) is H, halogen, nitrile, or a C₁₋₆alkyl group, said alkyl optionally substituted with 1-4 independent halogen; n is 0 or 1; and when R³ and R⁴ are connected to each other through X, then R³ and R⁴ are each C₁alkyl, and X is C₀₋₄alkyl. 